A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery
Abstract mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhib...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Tao, Qiangqiang [verfasserIn] |
|---|
| Format: |
E-Artikel |
|---|---|
| Sprache: |
Englisch |
| Erschienen: |
2020 |
|---|
| Schlagwörter: |
|---|
| Anmerkung: |
© Springer Science+Business Media, LLC, part of Springer Nature 2020 |
|---|
| Übergeordnetes Werk: |
Enthalten in: Medicinal chemistry research - Cambridge, Mass. [u.a.] : Birkhäuser Boston, 1991, 29(2020), 3 vom: 13. Jan., Seite 519-527 |
|---|---|
| Übergeordnetes Werk: |
volume:29 ; year:2020 ; number:3 ; day:13 ; month:01 ; pages:519-527 |
| Links: |
|---|
| DOI / URN: |
10.1007/s00044-020-02502-x |
|---|
| Katalog-ID: |
SPR00041994X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | SPR00041994X | ||
| 003 | DE-627 | ||
| 005 | 20230519224100.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 201001s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s00044-020-02502-x |2 doi | |
| 035 | |a (DE-627)SPR00041994X | ||
| 035 | |a (SPR)s00044-020-02502-x-e | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Tao, Qiangqiang |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a © Springer Science+Business Media, LLC, part of Springer Nature 2020 | ||
| 520 | |a Abstract mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with $ IC_{50} $ values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 ($ GI_{50} $ = 4.66 μM) and HCT116 ($ GI_{50} $ = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor. | ||
| 650 | 4 | |a Drug resistance |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Cross talk |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a mTOR/MEK bifunctional inhibitor |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a mTOR kinase inhibitor |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Allosteric MEK inhibitor |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Fang, Fang |4 aut | |
| 700 | 1 | |a Li, Jiaming |4 aut | |
| 700 | 1 | |a Wang, Yong |4 aut | |
| 700 | 1 | |a Zhao, Can |4 aut | |
| 700 | 1 | |a Liang, Jingtai |4 aut | |
| 700 | 1 | |a Ma, Xiaodong |4 aut | |
| 700 | 1 | |a Wang, Hao |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Medicinal chemistry research |d Cambridge, Mass. [u.a.] : Birkhäuser Boston, 1991 |g 29(2020), 3 vom: 13. Jan., Seite 519-527 |w (DE-627)490223427 |w (DE-600)2191978-1 |x 1554-8120 |7 nnns |
| 773 | 1 | 8 | |g volume:29 |g year:2020 |g number:3 |g day:13 |g month:01 |g pages:519-527 |
| 856 | 4 | 0 | |u https://dx.doi.org/10.1007/s00044-020-02502-x |z lizenzpflichtig |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a SYSFLAG_A | ||
| 912 | |a GBV_SPRINGER | ||
| 912 | |a SSG-OLC-PHA | ||
| 912 | |a GBV_ILN_11 | ||
| 912 | |a GBV_ILN_20 | ||
| 912 | |a GBV_ILN_22 | ||
| 912 | |a GBV_ILN_23 | ||
| 912 | |a GBV_ILN_24 | ||
| 912 | |a GBV_ILN_31 | ||
| 912 | |a GBV_ILN_32 | ||
| 912 | |a GBV_ILN_39 | ||
| 912 | |a GBV_ILN_40 | ||
| 912 | |a GBV_ILN_60 | ||
| 912 | |a GBV_ILN_62 | ||
| 912 | |a GBV_ILN_63 | ||
| 912 | |a GBV_ILN_65 | ||
| 912 | |a GBV_ILN_69 | ||
| 912 | |a GBV_ILN_70 | ||
| 912 | |a GBV_ILN_73 | ||
| 912 | |a GBV_ILN_74 | ||
| 912 | |a GBV_ILN_90 | ||
| 912 | |a GBV_ILN_95 | ||
| 912 | |a GBV_ILN_100 | ||
| 912 | |a GBV_ILN_101 | ||
| 912 | |a GBV_ILN_105 | ||
| 912 | |a GBV_ILN_110 | ||
| 912 | |a GBV_ILN_120 | ||
| 912 | |a GBV_ILN_138 | ||
| 912 | |a GBV_ILN_150 | ||
| 912 | |a GBV_ILN_151 | ||
| 912 | |a GBV_ILN_152 | ||
| 912 | |a GBV_ILN_161 | ||
| 912 | |a GBV_ILN_170 | ||
| 912 | |a GBV_ILN_171 | ||
| 912 | |a GBV_ILN_187 | ||
| 912 | |a GBV_ILN_213 | ||
| 912 | |a GBV_ILN_224 | ||
| 912 | |a GBV_ILN_230 | ||
| 912 | |a GBV_ILN_250 | ||
| 912 | |a GBV_ILN_281 | ||
| 912 | |a GBV_ILN_285 | ||
| 912 | |a GBV_ILN_293 | ||
| 912 | |a GBV_ILN_370 | ||
| 912 | |a GBV_ILN_602 | ||
| 912 | |a GBV_ILN_636 | ||
| 912 | |a GBV_ILN_702 | ||
| 912 | |a GBV_ILN_2001 | ||
| 912 | |a GBV_ILN_2003 | ||
| 912 | |a GBV_ILN_2004 | ||
| 912 | |a GBV_ILN_2005 | ||
| 912 | |a GBV_ILN_2006 | ||
| 912 | |a GBV_ILN_2007 | ||
| 912 | |a GBV_ILN_2008 | ||
| 912 | |a GBV_ILN_2009 | ||
| 912 | |a GBV_ILN_2010 | ||
| 912 | |a GBV_ILN_2011 | ||
| 912 | |a GBV_ILN_2014 | ||
| 912 | |a GBV_ILN_2015 | ||
| 912 | |a GBV_ILN_2020 | ||
| 912 | |a GBV_ILN_2021 | ||
| 912 | |a GBV_ILN_2025 | ||
| 912 | |a GBV_ILN_2026 | ||
| 912 | |a GBV_ILN_2027 | ||
| 912 | |a GBV_ILN_2031 | ||
| 912 | |a GBV_ILN_2034 | ||
| 912 | |a GBV_ILN_2037 | ||
| 912 | |a GBV_ILN_2038 | ||
| 912 | |a GBV_ILN_2039 | ||
| 912 | |a GBV_ILN_2044 | ||
| 912 | |a GBV_ILN_2048 | ||
| 912 | |a GBV_ILN_2049 | ||
| 912 | |a GBV_ILN_2050 | ||
| 912 | |a GBV_ILN_2055 | ||
| 912 | |a GBV_ILN_2056 | ||
| 912 | |a GBV_ILN_2057 | ||
| 912 | |a GBV_ILN_2059 | ||
| 912 | |a GBV_ILN_2061 | ||
| 912 | |a GBV_ILN_2064 | ||
| 912 | |a GBV_ILN_2065 | ||
| 912 | |a GBV_ILN_2068 | ||
| 912 | |a GBV_ILN_2088 | ||
| 912 | |a GBV_ILN_2093 | ||
| 912 | |a GBV_ILN_2106 | ||
| 912 | |a GBV_ILN_2107 | ||
| 912 | |a GBV_ILN_2108 | ||
| 912 | |a GBV_ILN_2110 | ||
| 912 | |a GBV_ILN_2111 | ||
| 912 | |a GBV_ILN_2112 | ||
| 912 | |a GBV_ILN_2113 | ||
| 912 | |a GBV_ILN_2118 | ||
| 912 | |a GBV_ILN_2122 | ||
| 912 | |a GBV_ILN_2129 | ||
| 912 | |a GBV_ILN_2143 | ||
| 912 | |a GBV_ILN_2144 | ||
| 912 | |a GBV_ILN_2147 | ||
| 912 | |a GBV_ILN_2148 | ||
| 912 | |a GBV_ILN_2152 | ||
| 912 | |a GBV_ILN_2153 | ||
| 912 | |a GBV_ILN_2188 | ||
| 912 | |a GBV_ILN_2190 | ||
| 912 | |a GBV_ILN_2232 | ||
| 912 | |a GBV_ILN_2336 | ||
| 912 | |a GBV_ILN_2446 | ||
| 912 | |a GBV_ILN_2470 | ||
| 912 | |a GBV_ILN_2472 | ||
| 912 | |a GBV_ILN_2507 | ||
| 912 | |a GBV_ILN_2522 | ||
| 912 | |a GBV_ILN_2548 | ||
| 912 | |a GBV_ILN_4035 | ||
| 912 | |a GBV_ILN_4037 | ||
| 912 | |a GBV_ILN_4046 | ||
| 912 | |a GBV_ILN_4112 | ||
| 912 | |a GBV_ILN_4125 | ||
| 912 | |a GBV_ILN_4126 | ||
| 912 | |a GBV_ILN_4242 | ||
| 912 | |a GBV_ILN_4246 | ||
| 912 | |a GBV_ILN_4249 | ||
| 912 | |a GBV_ILN_4251 | ||
| 912 | |a GBV_ILN_4305 | ||
| 912 | |a GBV_ILN_4306 | ||
| 912 | |a GBV_ILN_4307 | ||
| 912 | |a GBV_ILN_4313 | ||
| 912 | |a GBV_ILN_4322 | ||
| 912 | |a GBV_ILN_4323 | ||
| 912 | |a GBV_ILN_4324 | ||
| 912 | |a GBV_ILN_4325 | ||
| 912 | |a GBV_ILN_4326 | ||
| 912 | |a GBV_ILN_4328 | ||
| 912 | |a GBV_ILN_4333 | ||
| 912 | |a GBV_ILN_4334 | ||
| 912 | |a GBV_ILN_4335 | ||
| 912 | |a GBV_ILN_4336 | ||
| 912 | |a GBV_ILN_4338 | ||
| 912 | |a GBV_ILN_4393 | ||
| 912 | |a GBV_ILN_4700 | ||
| 951 | |a AR | ||
| 952 | |d 29 |j 2020 |e 3 |b 13 |c 01 |h 519-527 | ||
| author_variant |
q t qt f f ff j l jl y w yw c z cz j l jl x m xm h w hw |
|---|---|
| matchkey_str |
article:15548120:2020----::cnuaemomkiucinlniioaptniloyhraooiaatcneaet |
| hierarchy_sort_str |
2020 |
| publishDate |
2020 |
| allfields |
10.1007/s00044-020-02502-x doi (DE-627)SPR00041994X (SPR)s00044-020-02502-x-e DE-627 ger DE-627 rakwb eng Tao, Qiangqiang verfasserin aut A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with $ IC_{50} $ values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 ($ GI_{50} $ = 4.66 μM) and HCT116 ($ GI_{50} $ = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor. Drug resistance (dpeaa)DE-He213 Cross talk (dpeaa)DE-He213 mTOR/MEK bifunctional inhibitor (dpeaa)DE-He213 mTOR kinase inhibitor (dpeaa)DE-He213 Allosteric MEK inhibitor (dpeaa)DE-He213 Fang, Fang aut Li, Jiaming aut Wang, Yong aut Zhao, Can aut Liang, Jingtai aut Ma, Xiaodong aut Wang, Hao aut Enthalten in Medicinal chemistry research Cambridge, Mass. [u.a.] : Birkhäuser Boston, 1991 29(2020), 3 vom: 13. Jan., Seite 519-527 (DE-627)490223427 (DE-600)2191978-1 1554-8120 nnns volume:29 year:2020 number:3 day:13 month:01 pages:519-527 https://dx.doi.org/10.1007/s00044-020-02502-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 29 2020 3 13 01 519-527 |
| spelling |
10.1007/s00044-020-02502-x doi (DE-627)SPR00041994X (SPR)s00044-020-02502-x-e DE-627 ger DE-627 rakwb eng Tao, Qiangqiang verfasserin aut A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with $ IC_{50} $ values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 ($ GI_{50} $ = 4.66 μM) and HCT116 ($ GI_{50} $ = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor. Drug resistance (dpeaa)DE-He213 Cross talk (dpeaa)DE-He213 mTOR/MEK bifunctional inhibitor (dpeaa)DE-He213 mTOR kinase inhibitor (dpeaa)DE-He213 Allosteric MEK inhibitor (dpeaa)DE-He213 Fang, Fang aut Li, Jiaming aut Wang, Yong aut Zhao, Can aut Liang, Jingtai aut Ma, Xiaodong aut Wang, Hao aut Enthalten in Medicinal chemistry research Cambridge, Mass. [u.a.] : Birkhäuser Boston, 1991 29(2020), 3 vom: 13. Jan., Seite 519-527 (DE-627)490223427 (DE-600)2191978-1 1554-8120 nnns volume:29 year:2020 number:3 day:13 month:01 pages:519-527 https://dx.doi.org/10.1007/s00044-020-02502-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 29 2020 3 13 01 519-527 |
| allfields_unstemmed |
10.1007/s00044-020-02502-x doi (DE-627)SPR00041994X (SPR)s00044-020-02502-x-e DE-627 ger DE-627 rakwb eng Tao, Qiangqiang verfasserin aut A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with $ IC_{50} $ values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 ($ GI_{50} $ = 4.66 μM) and HCT116 ($ GI_{50} $ = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor. Drug resistance (dpeaa)DE-He213 Cross talk (dpeaa)DE-He213 mTOR/MEK bifunctional inhibitor (dpeaa)DE-He213 mTOR kinase inhibitor (dpeaa)DE-He213 Allosteric MEK inhibitor (dpeaa)DE-He213 Fang, Fang aut Li, Jiaming aut Wang, Yong aut Zhao, Can aut Liang, Jingtai aut Ma, Xiaodong aut Wang, Hao aut Enthalten in Medicinal chemistry research Cambridge, Mass. [u.a.] : Birkhäuser Boston, 1991 29(2020), 3 vom: 13. Jan., Seite 519-527 (DE-627)490223427 (DE-600)2191978-1 1554-8120 nnns volume:29 year:2020 number:3 day:13 month:01 pages:519-527 https://dx.doi.org/10.1007/s00044-020-02502-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 29 2020 3 13 01 519-527 |
| allfieldsGer |
10.1007/s00044-020-02502-x doi (DE-627)SPR00041994X (SPR)s00044-020-02502-x-e DE-627 ger DE-627 rakwb eng Tao, Qiangqiang verfasserin aut A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with $ IC_{50} $ values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 ($ GI_{50} $ = 4.66 μM) and HCT116 ($ GI_{50} $ = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor. Drug resistance (dpeaa)DE-He213 Cross talk (dpeaa)DE-He213 mTOR/MEK bifunctional inhibitor (dpeaa)DE-He213 mTOR kinase inhibitor (dpeaa)DE-He213 Allosteric MEK inhibitor (dpeaa)DE-He213 Fang, Fang aut Li, Jiaming aut Wang, Yong aut Zhao, Can aut Liang, Jingtai aut Ma, Xiaodong aut Wang, Hao aut Enthalten in Medicinal chemistry research Cambridge, Mass. [u.a.] : Birkhäuser Boston, 1991 29(2020), 3 vom: 13. Jan., Seite 519-527 (DE-627)490223427 (DE-600)2191978-1 1554-8120 nnns volume:29 year:2020 number:3 day:13 month:01 pages:519-527 https://dx.doi.org/10.1007/s00044-020-02502-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 29 2020 3 13 01 519-527 |
| allfieldsSound |
10.1007/s00044-020-02502-x doi (DE-627)SPR00041994X (SPR)s00044-020-02502-x-e DE-627 ger DE-627 rakwb eng Tao, Qiangqiang verfasserin aut A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with $ IC_{50} $ values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 ($ GI_{50} $ = 4.66 μM) and HCT116 ($ GI_{50} $ = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor. Drug resistance (dpeaa)DE-He213 Cross talk (dpeaa)DE-He213 mTOR/MEK bifunctional inhibitor (dpeaa)DE-He213 mTOR kinase inhibitor (dpeaa)DE-He213 Allosteric MEK inhibitor (dpeaa)DE-He213 Fang, Fang aut Li, Jiaming aut Wang, Yong aut Zhao, Can aut Liang, Jingtai aut Ma, Xiaodong aut Wang, Hao aut Enthalten in Medicinal chemistry research Cambridge, Mass. [u.a.] : Birkhäuser Boston, 1991 29(2020), 3 vom: 13. Jan., Seite 519-527 (DE-627)490223427 (DE-600)2191978-1 1554-8120 nnns volume:29 year:2020 number:3 day:13 month:01 pages:519-527 https://dx.doi.org/10.1007/s00044-020-02502-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 29 2020 3 13 01 519-527 |
| language |
English |
| source |
Enthalten in Medicinal chemistry research 29(2020), 3 vom: 13. Jan., Seite 519-527 volume:29 year:2020 number:3 day:13 month:01 pages:519-527 |
| sourceStr |
Enthalten in Medicinal chemistry research 29(2020), 3 vom: 13. Jan., Seite 519-527 volume:29 year:2020 number:3 day:13 month:01 pages:519-527 |
| format_phy_str_mv |
Article |
| institution |
findex.gbv.de |
| topic_facet |
Drug resistance Cross talk mTOR/MEK bifunctional inhibitor mTOR kinase inhibitor Allosteric MEK inhibitor |
| isfreeaccess_bool |
false |
| container_title |
Medicinal chemistry research |
| authorswithroles_txt_mv |
Tao, Qiangqiang @@aut@@ Fang, Fang @@aut@@ Li, Jiaming @@aut@@ Wang, Yong @@aut@@ Zhao, Can @@aut@@ Liang, Jingtai @@aut@@ Ma, Xiaodong @@aut@@ Wang, Hao @@aut@@ |
| publishDateDaySort_date |
2020-01-13T00:00:00Z |
| hierarchy_top_id |
490223427 |
| id |
SPR00041994X |
| language_de |
englisch |
| fullrecord |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR00041994X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230519224100.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201001s2020 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1007/s00044-020-02502-x</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR00041994X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s00044-020-02502-x-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Tao, Qiangqiang</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="2"><subfield code="a">A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2020</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© Springer Science+Business Media, LLC, part of Springer Nature 2020</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with $ IC_{50} $ values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 ($ GI_{50} $ = 4.66 μM) and HCT116 ($ GI_{50} $ = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Drug resistance</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cross talk</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mTOR/MEK bifunctional inhibitor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mTOR kinase inhibitor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Allosteric MEK inhibitor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Fang, Fang</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Li, Jiaming</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Yong</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zhao, Can</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Liang, Jingtai</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Ma, Xiaodong</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Hao</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Medicinal chemistry research</subfield><subfield code="d">Cambridge, Mass. [u.a.] : Birkhäuser Boston, 1991</subfield><subfield code="g">29(2020), 3 vom: 13. Jan., Seite 519-527</subfield><subfield code="w">(DE-627)490223427</subfield><subfield code="w">(DE-600)2191978-1</subfield><subfield code="x">1554-8120</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:29</subfield><subfield code="g">year:2020</subfield><subfield code="g">number:3</subfield><subfield code="g">day:13</subfield><subfield code="g">month:01</subfield><subfield code="g">pages:519-527</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://dx.doi.org/10.1007/s00044-020-02502-x</subfield><subfield code="z">lizenzpflichtig</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_SPRINGER</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_11</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_31</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_32</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_90</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_100</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_101</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_120</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_138</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_150</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_152</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_171</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_187</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_224</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_250</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_281</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_370</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_636</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_702</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2001</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2003</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2004</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2006</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2007</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2008</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2009</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2010</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2011</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2015</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2020</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2021</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2025</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2026</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2027</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2031</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2034</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2038</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2039</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2044</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2048</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2049</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2050</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2055</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2056</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2057</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2059</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2061</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2064</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2065</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2068</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2088</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2093</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2106</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2107</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2108</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2111</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2113</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2118</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2122</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2129</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2143</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2144</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2147</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2148</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2152</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2153</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2188</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2190</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2232</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2336</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2446</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2470</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2472</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2507</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2522</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2548</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4035</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4046</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4242</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4246</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4251</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4326</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4328</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4333</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4334</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4335</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4336</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4393</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">29</subfield><subfield code="j">2020</subfield><subfield code="e">3</subfield><subfield code="b">13</subfield><subfield code="c">01</subfield><subfield code="h">519-527</subfield></datafield></record></collection>
|
| author |
Tao, Qiangqiang |
| spellingShingle |
Tao, Qiangqiang misc Drug resistance misc Cross talk misc mTOR/MEK bifunctional inhibitor misc mTOR kinase inhibitor misc Allosteric MEK inhibitor A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery |
| authorStr |
Tao, Qiangqiang |
| ppnlink_with_tag_str_mv |
@@773@@(DE-627)490223427 |
| format |
electronic Article |
| delete_txt_mv |
keep |
| author_role |
aut aut aut aut aut aut aut aut |
| collection |
springer |
| remote_str |
true |
| illustrated |
Not Illustrated |
| issn |
1554-8120 |
| topic_title |
A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery Drug resistance (dpeaa)DE-He213 Cross talk (dpeaa)DE-He213 mTOR/MEK bifunctional inhibitor (dpeaa)DE-He213 mTOR kinase inhibitor (dpeaa)DE-He213 Allosteric MEK inhibitor (dpeaa)DE-He213 |
| topic |
misc Drug resistance misc Cross talk misc mTOR/MEK bifunctional inhibitor misc mTOR kinase inhibitor misc Allosteric MEK inhibitor |
| topic_unstemmed |
misc Drug resistance misc Cross talk misc mTOR/MEK bifunctional inhibitor misc mTOR kinase inhibitor misc Allosteric MEK inhibitor |
| topic_browse |
misc Drug resistance misc Cross talk misc mTOR/MEK bifunctional inhibitor misc mTOR kinase inhibitor misc Allosteric MEK inhibitor |
| format_facet |
Elektronische Aufsätze Aufsätze Elektronische Ressource |
| format_main_str_mv |
Text Zeitschrift/Artikel |
| carriertype_str_mv |
cr |
| hierarchy_parent_title |
Medicinal chemistry research |
| hierarchy_parent_id |
490223427 |
| hierarchy_top_title |
Medicinal chemistry research |
| isfreeaccess_txt |
false |
| familylinks_str_mv |
(DE-627)490223427 (DE-600)2191978-1 |
| title |
A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery |
| ctrlnum |
(DE-627)SPR00041994X (SPR)s00044-020-02502-x-e |
| title_full |
A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery |
| author_sort |
Tao, Qiangqiang |
| journal |
Medicinal chemistry research |
| journalStr |
Medicinal chemistry research |
| lang_code |
eng |
| isOA_bool |
false |
| recordtype |
marc |
| publishDateSort |
2020 |
| contenttype_str_mv |
txt |
| container_start_page |
519 |
| author_browse |
Tao, Qiangqiang Fang, Fang Li, Jiaming Wang, Yong Zhao, Can Liang, Jingtai Ma, Xiaodong Wang, Hao |
| container_volume |
29 |
| format_se |
Elektronische Aufsätze |
| author-letter |
Tao, Qiangqiang |
| doi_str_mv |
10.1007/s00044-020-02502-x |
| title_sort |
conjugated mtor/mek bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery |
| title_auth |
A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery |
| abstract |
Abstract mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with $ IC_{50} $ values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 ($ GI_{50} $ = 4.66 μM) and HCT116 ($ GI_{50} $ = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor. © Springer Science+Business Media, LLC, part of Springer Nature 2020 |
| abstractGer |
Abstract mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with $ IC_{50} $ values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 ($ GI_{50} $ = 4.66 μM) and HCT116 ($ GI_{50} $ = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor. © Springer Science+Business Media, LLC, part of Springer Nature 2020 |
| abstract_unstemmed |
Abstract mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with $ IC_{50} $ values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 ($ GI_{50} $ = 4.66 μM) and HCT116 ($ GI_{50} $ = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor. © Springer Science+Business Media, LLC, part of Springer Nature 2020 |
| collection_details |
GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 |
| container_issue |
3 |
| title_short |
A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery |
| url |
https://dx.doi.org/10.1007/s00044-020-02502-x |
| remote_bool |
true |
| author2 |
Fang, Fang Li, Jiaming Wang, Yong Zhao, Can Liang, Jingtai Ma, Xiaodong Wang, Hao |
| author2Str |
Fang, Fang Li, Jiaming Wang, Yong Zhao, Can Liang, Jingtai Ma, Xiaodong Wang, Hao |
| ppnlink |
490223427 |
| mediatype_str_mv |
c |
| isOA_txt |
false |
| hochschulschrift_bool |
false |
| doi_str |
10.1007/s00044-020-02502-x |
| up_date |
2024-07-03T15:58:20.971Z |
| _version_ |
1803574104266113024 |
| fullrecord_marcxml |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR00041994X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230519224100.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201001s2020 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1007/s00044-020-02502-x</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR00041994X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s00044-020-02502-x-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Tao, Qiangqiang</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="2"><subfield code="a">A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2020</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© Springer Science+Business Media, LLC, part of Springer Nature 2020</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with $ IC_{50} $ values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 ($ GI_{50} $ = 4.66 μM) and HCT116 ($ GI_{50} $ = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Drug resistance</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cross talk</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mTOR/MEK bifunctional inhibitor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mTOR kinase inhibitor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Allosteric MEK inhibitor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Fang, Fang</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Li, Jiaming</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Yong</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zhao, Can</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Liang, Jingtai</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Ma, Xiaodong</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Hao</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Medicinal chemistry research</subfield><subfield code="d">Cambridge, Mass. [u.a.] : Birkhäuser Boston, 1991</subfield><subfield code="g">29(2020), 3 vom: 13. Jan., Seite 519-527</subfield><subfield code="w">(DE-627)490223427</subfield><subfield code="w">(DE-600)2191978-1</subfield><subfield code="x">1554-8120</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:29</subfield><subfield code="g">year:2020</subfield><subfield code="g">number:3</subfield><subfield code="g">day:13</subfield><subfield code="g">month:01</subfield><subfield code="g">pages:519-527</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://dx.doi.org/10.1007/s00044-020-02502-x</subfield><subfield code="z">lizenzpflichtig</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_SPRINGER</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_11</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_31</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_32</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_90</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_100</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_101</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_120</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_138</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_150</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_152</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_171</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_187</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_224</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_250</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_281</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_370</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_636</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_702</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2001</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2003</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2004</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2006</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2007</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2008</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2009</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2010</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2011</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2015</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2020</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2021</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2025</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2026</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2027</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2031</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2034</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2038</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2039</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2044</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2048</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2049</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2050</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2055</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2056</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2057</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2059</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2061</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2064</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2065</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2068</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2088</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2093</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2106</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2107</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2108</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2111</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2113</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2118</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2122</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2129</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2143</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2144</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2147</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2148</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2152</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2153</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2188</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2190</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2232</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2336</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2446</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2470</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2472</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2507</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2522</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2548</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4035</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4046</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4242</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4246</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4251</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4326</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4328</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4333</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4334</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4335</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4336</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4393</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">29</subfield><subfield code="j">2020</subfield><subfield code="e">3</subfield><subfield code="b">13</subfield><subfield code="c">01</subfield><subfield code="h">519-527</subfield></datafield></record></collection>
|
| score |
7.396736 |