Discovery of novel triazolo[4,3-
PIM kinase family (PIM-1, PIM-2 and PIM-3) is an appealing target for the discovery and development of selective inhibitors, useful in various disease conditions in which these proteins are highly expressed, such as cancer. The significant effort put, in the recent years, towards the development of...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Martínez-González, Sonia [verfasserIn] Rodríguez-Arístegui, Sonsoles [verfasserIn] Gómez de la Oliva, Cristina Ana [verfasserIn] Hernández, Ana Isabel [verfasserIn] González Cantalapiedra, Esther [verfasserIn] Varela, Carmen [verfasserIn] García, Ana Belén [verfasserIn] Rabal, Obdulia [verfasserIn] Oyarzabal, Julen [verfasserIn] Bischoff, James R. [verfasserIn] Klett, Javier [verfasserIn] Albarrán, María Isabel [verfasserIn] Cebriá, Antonio [verfasserIn] Ajenjo, Nuria [verfasserIn] García-Serelde, Beatriz [verfasserIn] Gómez-Casero, Elena [verfasserIn] Cuadrado-Urbano, Manuel [verfasserIn] Cebrián, David [verfasserIn] Blanco-Aparicio, Carmen [verfasserIn] Pastor, Joaquín [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2019 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: European journal of medicinal chemistry - Amsterdam [u.a.] : Elsevier Science, 1987, 168, Seite 87-109 |
|---|---|
| Übergeordnetes Werk: |
volume:168 ; pages:87-109 |
| DOI / URN: |
10.1016/j.ejmech.2019.02.022 |
|---|
| Katalog-ID: |
ELV001862634 |
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| 100 | 1 | |a Martínez-González, Sonia |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of novel triazolo[4,3- |
| 264 | 1 | |c 2019 | |
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| 520 | |a PIM kinase family (PIM-1, PIM-2 and PIM-3) is an appealing target for the discovery and development of selective inhibitors, useful in various disease conditions in which these proteins are highly expressed, such as cancer. The significant effort put, in the recent years, towards the development of small molecules exhibiting inhibitory activity against this protein family has ended up with several molecules entering clinical trials. As part of our ongoing exploration for potential drug candidates that exhibit affinity towards this protein family, we have generated a novel chemical series of triazolo[4,3-b]pyridazine based tricycles by applying a scaffold hopping strategy over our previously reported potent pan-PIM inhibitor ETP-47453 (compound 2). The structure-activity relationship studies presented herein demonstrate a rather selective PIM-1/PIM-3 biochemical profile for this novel series of tricycles, although pan-PIM and PIM-1 inhibitors have also been identified. Selected examples show significant inhibition of the phosphorylation of BAD protein in a cell-based assay. Moreover, optimized and highly selective compounds, such as 42, did not show significant hERG inhibition at 20 μM concentration, and proved its antiproliferative activity and utility in combination with particular antitumoral agents in several tumor cell lines. | ||
| 650 | 4 | |a Anticancer agents | |
| 650 | 4 | |a Selective PIM-1/PIM-3 inhibitors | |
| 650 | 4 | |a pan-PIM inhibitors | |
| 650 | 4 | |a PIM-1 inhibitors | |
| 650 | 4 | |a Chemical probes | |
| 650 | 4 | |a Antiproliferative activity | |
| 650 | 4 | |a Synergistic effects | |
| 700 | 1 | |a Rodríguez-Arístegui, Sonsoles |e verfasserin |4 aut | |
| 700 | 1 | |a Gómez de la Oliva, Cristina Ana |e verfasserin |4 aut | |
| 700 | 1 | |a Hernández, Ana Isabel |e verfasserin |4 aut | |
| 700 | 1 | |a González Cantalapiedra, Esther |e verfasserin |4 aut | |
| 700 | 1 | |a Varela, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a García, Ana Belén |e verfasserin |4 aut | |
| 700 | 1 | |a Rabal, Obdulia |e verfasserin |4 aut | |
| 700 | 1 | |a Oyarzabal, Julen |e verfasserin |0 (orcid)0000-0003-1941-7255 |4 aut | |
| 700 | 1 | |a Bischoff, James R. |e verfasserin |4 aut | |
| 700 | 1 | |a Klett, Javier |e verfasserin |4 aut | |
| 700 | 1 | |a Albarrán, María Isabel |e verfasserin |4 aut | |
| 700 | 1 | |a Cebriá, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Ajenjo, Nuria |e verfasserin |4 aut | |
| 700 | 1 | |a García-Serelde, Beatriz |e verfasserin |4 aut | |
| 700 | 1 | |a Gómez-Casero, Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Cuadrado-Urbano, Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Cebrián, David |e verfasserin |4 aut | |
| 700 | 1 | |a Blanco-Aparicio, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a Pastor, Joaquín |e verfasserin |0 (orcid)0000-0003-0553-8021 |4 aut | |
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10.1016/j.ejmech.2019.02.022 doi (DE-627)ELV001862634 (ELSEVIER)S0223-5234(19)30136-9 DE-627 ger DE-627 rda eng 610 DE-600 15,3 ssgn PHARM DE-84 fid 44.42 bkl Martínez-González, Sonia verfasserin aut Discovery of novel triazolo[4,3- 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier PIM kinase family (PIM-1, PIM-2 and PIM-3) is an appealing target for the discovery and development of selective inhibitors, useful in various disease conditions in which these proteins are highly expressed, such as cancer. The significant effort put, in the recent years, towards the development of small molecules exhibiting inhibitory activity against this protein family has ended up with several molecules entering clinical trials. As part of our ongoing exploration for potential drug candidates that exhibit affinity towards this protein family, we have generated a novel chemical series of triazolo[4,3-b]pyridazine based tricycles by applying a scaffold hopping strategy over our previously reported potent pan-PIM inhibitor ETP-47453 (compound 2). The structure-activity relationship studies presented herein demonstrate a rather selective PIM-1/PIM-3 biochemical profile for this novel series of tricycles, although pan-PIM and PIM-1 inhibitors have also been identified. Selected examples show significant inhibition of the phosphorylation of BAD protein in a cell-based assay. Moreover, optimized and highly selective compounds, such as 42, did not show significant hERG inhibition at 20 μM concentration, and proved its antiproliferative activity and utility in combination with particular antitumoral agents in several tumor cell lines. Anticancer agents Selective PIM-1/PIM-3 inhibitors pan-PIM inhibitors PIM-1 inhibitors Chemical probes Antiproliferative activity Synergistic effects Rodríguez-Arístegui, Sonsoles verfasserin aut Gómez de la Oliva, Cristina Ana verfasserin aut Hernández, Ana Isabel verfasserin aut González Cantalapiedra, Esther verfasserin aut Varela, Carmen verfasserin aut García, Ana Belén verfasserin aut Rabal, Obdulia verfasserin aut Oyarzabal, Julen verfasserin (orcid)0000-0003-1941-7255 aut Bischoff, James R. verfasserin aut Klett, Javier verfasserin aut Albarrán, María Isabel verfasserin aut Cebriá, Antonio verfasserin aut Ajenjo, Nuria verfasserin aut García-Serelde, Beatriz verfasserin aut Gómez-Casero, Elena verfasserin aut Cuadrado-Urbano, Manuel verfasserin aut Cebrián, David verfasserin aut Blanco-Aparicio, Carmen verfasserin aut Pastor, Joaquín verfasserin (orcid)0000-0003-0553-8021 aut Enthalten in European journal of medicinal chemistry Amsterdam [u.a.] : Elsevier Science, 1987 168, Seite 87-109 Online-Ressource (DE-627)320443213 (DE-600)2005170-0 (DE-576)25927125X 1768-3254 nnns volume:168 pages:87-109 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 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_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.42 Pharmazeutische Chemie AR 168 87-109 |
| spelling |
10.1016/j.ejmech.2019.02.022 doi (DE-627)ELV001862634 (ELSEVIER)S0223-5234(19)30136-9 DE-627 ger DE-627 rda eng 610 DE-600 15,3 ssgn PHARM DE-84 fid 44.42 bkl Martínez-González, Sonia verfasserin aut Discovery of novel triazolo[4,3- 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier PIM kinase family (PIM-1, PIM-2 and PIM-3) is an appealing target for the discovery and development of selective inhibitors, useful in various disease conditions in which these proteins are highly expressed, such as cancer. The significant effort put, in the recent years, towards the development of small molecules exhibiting inhibitory activity against this protein family has ended up with several molecules entering clinical trials. As part of our ongoing exploration for potential drug candidates that exhibit affinity towards this protein family, we have generated a novel chemical series of triazolo[4,3-b]pyridazine based tricycles by applying a scaffold hopping strategy over our previously reported potent pan-PIM inhibitor ETP-47453 (compound 2). The structure-activity relationship studies presented herein demonstrate a rather selective PIM-1/PIM-3 biochemical profile for this novel series of tricycles, although pan-PIM and PIM-1 inhibitors have also been identified. Selected examples show significant inhibition of the phosphorylation of BAD protein in a cell-based assay. Moreover, optimized and highly selective compounds, such as 42, did not show significant hERG inhibition at 20 μM concentration, and proved its antiproliferative activity and utility in combination with particular antitumoral agents in several tumor cell lines. Anticancer agents Selective PIM-1/PIM-3 inhibitors pan-PIM inhibitors PIM-1 inhibitors Chemical probes Antiproliferative activity Synergistic effects Rodríguez-Arístegui, Sonsoles verfasserin aut Gómez de la Oliva, Cristina Ana verfasserin aut Hernández, Ana Isabel verfasserin aut González Cantalapiedra, Esther verfasserin aut Varela, Carmen verfasserin aut García, Ana Belén verfasserin aut Rabal, Obdulia verfasserin aut Oyarzabal, Julen verfasserin (orcid)0000-0003-1941-7255 aut Bischoff, James R. verfasserin aut Klett, Javier verfasserin aut Albarrán, María Isabel verfasserin aut Cebriá, Antonio verfasserin aut Ajenjo, Nuria verfasserin aut García-Serelde, Beatriz verfasserin aut Gómez-Casero, Elena verfasserin aut Cuadrado-Urbano, Manuel verfasserin aut Cebrián, David verfasserin aut Blanco-Aparicio, Carmen verfasserin aut Pastor, Joaquín verfasserin (orcid)0000-0003-0553-8021 aut Enthalten in European journal of medicinal chemistry Amsterdam [u.a.] : Elsevier Science, 1987 168, Seite 87-109 Online-Ressource (DE-627)320443213 (DE-600)2005170-0 (DE-576)25927125X 1768-3254 nnns volume:168 pages:87-109 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 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_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.42 Pharmazeutische Chemie AR 168 87-109 |
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10.1016/j.ejmech.2019.02.022 doi (DE-627)ELV001862634 (ELSEVIER)S0223-5234(19)30136-9 DE-627 ger DE-627 rda eng 610 DE-600 15,3 ssgn PHARM DE-84 fid 44.42 bkl Martínez-González, Sonia verfasserin aut Discovery of novel triazolo[4,3- 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier PIM kinase family (PIM-1, PIM-2 and PIM-3) is an appealing target for the discovery and development of selective inhibitors, useful in various disease conditions in which these proteins are highly expressed, such as cancer. The significant effort put, in the recent years, towards the development of small molecules exhibiting inhibitory activity against this protein family has ended up with several molecules entering clinical trials. As part of our ongoing exploration for potential drug candidates that exhibit affinity towards this protein family, we have generated a novel chemical series of triazolo[4,3-b]pyridazine based tricycles by applying a scaffold hopping strategy over our previously reported potent pan-PIM inhibitor ETP-47453 (compound 2). The structure-activity relationship studies presented herein demonstrate a rather selective PIM-1/PIM-3 biochemical profile for this novel series of tricycles, although pan-PIM and PIM-1 inhibitors have also been identified. Selected examples show significant inhibition of the phosphorylation of BAD protein in a cell-based assay. Moreover, optimized and highly selective compounds, such as 42, did not show significant hERG inhibition at 20 μM concentration, and proved its antiproliferative activity and utility in combination with particular antitumoral agents in several tumor cell lines. Anticancer agents Selective PIM-1/PIM-3 inhibitors pan-PIM inhibitors PIM-1 inhibitors Chemical probes Antiproliferative activity Synergistic effects Rodríguez-Arístegui, Sonsoles verfasserin aut Gómez de la Oliva, Cristina Ana verfasserin aut Hernández, Ana Isabel verfasserin aut González Cantalapiedra, Esther verfasserin aut Varela, Carmen verfasserin aut García, Ana Belén verfasserin aut Rabal, Obdulia verfasserin aut Oyarzabal, Julen verfasserin (orcid)0000-0003-1941-7255 aut Bischoff, James R. verfasserin aut Klett, Javier verfasserin aut Albarrán, María Isabel verfasserin aut Cebriá, Antonio verfasserin aut Ajenjo, Nuria verfasserin aut García-Serelde, Beatriz verfasserin aut Gómez-Casero, Elena verfasserin aut Cuadrado-Urbano, Manuel verfasserin aut Cebrián, David verfasserin aut Blanco-Aparicio, Carmen verfasserin aut Pastor, Joaquín verfasserin (orcid)0000-0003-0553-8021 aut Enthalten in European journal of medicinal chemistry Amsterdam [u.a.] : Elsevier Science, 1987 168, Seite 87-109 Online-Ressource (DE-627)320443213 (DE-600)2005170-0 (DE-576)25927125X 1768-3254 nnns volume:168 pages:87-109 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 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_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.42 Pharmazeutische Chemie AR 168 87-109 |
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10.1016/j.ejmech.2019.02.022 doi (DE-627)ELV001862634 (ELSEVIER)S0223-5234(19)30136-9 DE-627 ger DE-627 rda eng 610 DE-600 15,3 ssgn PHARM DE-84 fid 44.42 bkl Martínez-González, Sonia verfasserin aut Discovery of novel triazolo[4,3- 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier PIM kinase family (PIM-1, PIM-2 and PIM-3) is an appealing target for the discovery and development of selective inhibitors, useful in various disease conditions in which these proteins are highly expressed, such as cancer. The significant effort put, in the recent years, towards the development of small molecules exhibiting inhibitory activity against this protein family has ended up with several molecules entering clinical trials. As part of our ongoing exploration for potential drug candidates that exhibit affinity towards this protein family, we have generated a novel chemical series of triazolo[4,3-b]pyridazine based tricycles by applying a scaffold hopping strategy over our previously reported potent pan-PIM inhibitor ETP-47453 (compound 2). The structure-activity relationship studies presented herein demonstrate a rather selective PIM-1/PIM-3 biochemical profile for this novel series of tricycles, although pan-PIM and PIM-1 inhibitors have also been identified. Selected examples show significant inhibition of the phosphorylation of BAD protein in a cell-based assay. Moreover, optimized and highly selective compounds, such as 42, did not show significant hERG inhibition at 20 μM concentration, and proved its antiproliferative activity and utility in combination with particular antitumoral agents in several tumor cell lines. Anticancer agents Selective PIM-1/PIM-3 inhibitors pan-PIM inhibitors PIM-1 inhibitors Chemical probes Antiproliferative activity Synergistic effects Rodríguez-Arístegui, Sonsoles verfasserin aut Gómez de la Oliva, Cristina Ana verfasserin aut Hernández, Ana Isabel verfasserin aut González Cantalapiedra, Esther verfasserin aut Varela, Carmen verfasserin aut García, Ana Belén verfasserin aut Rabal, Obdulia verfasserin aut Oyarzabal, Julen verfasserin (orcid)0000-0003-1941-7255 aut Bischoff, James R. verfasserin aut Klett, Javier verfasserin aut Albarrán, María Isabel verfasserin aut Cebriá, Antonio verfasserin aut Ajenjo, Nuria verfasserin aut García-Serelde, Beatriz verfasserin aut Gómez-Casero, Elena verfasserin aut Cuadrado-Urbano, Manuel verfasserin aut Cebrián, David verfasserin aut Blanco-Aparicio, Carmen verfasserin aut Pastor, Joaquín verfasserin (orcid)0000-0003-0553-8021 aut Enthalten in European journal of medicinal chemistry Amsterdam [u.a.] : Elsevier Science, 1987 168, Seite 87-109 Online-Ressource (DE-627)320443213 (DE-600)2005170-0 (DE-576)25927125X 1768-3254 nnns volume:168 pages:87-109 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 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_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.42 Pharmazeutische Chemie AR 168 87-109 |
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10.1016/j.ejmech.2019.02.022 doi (DE-627)ELV001862634 (ELSEVIER)S0223-5234(19)30136-9 DE-627 ger DE-627 rda eng 610 DE-600 15,3 ssgn PHARM DE-84 fid 44.42 bkl Martínez-González, Sonia verfasserin aut Discovery of novel triazolo[4,3- 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier PIM kinase family (PIM-1, PIM-2 and PIM-3) is an appealing target for the discovery and development of selective inhibitors, useful in various disease conditions in which these proteins are highly expressed, such as cancer. The significant effort put, in the recent years, towards the development of small molecules exhibiting inhibitory activity against this protein family has ended up with several molecules entering clinical trials. As part of our ongoing exploration for potential drug candidates that exhibit affinity towards this protein family, we have generated a novel chemical series of triazolo[4,3-b]pyridazine based tricycles by applying a scaffold hopping strategy over our previously reported potent pan-PIM inhibitor ETP-47453 (compound 2). The structure-activity relationship studies presented herein demonstrate a rather selective PIM-1/PIM-3 biochemical profile for this novel series of tricycles, although pan-PIM and PIM-1 inhibitors have also been identified. Selected examples show significant inhibition of the phosphorylation of BAD protein in a cell-based assay. Moreover, optimized and highly selective compounds, such as 42, did not show significant hERG inhibition at 20 μM concentration, and proved its antiproliferative activity and utility in combination with particular antitumoral agents in several tumor cell lines. Anticancer agents Selective PIM-1/PIM-3 inhibitors pan-PIM inhibitors PIM-1 inhibitors Chemical probes Antiproliferative activity Synergistic effects Rodríguez-Arístegui, Sonsoles verfasserin aut Gómez de la Oliva, Cristina Ana verfasserin aut Hernández, Ana Isabel verfasserin aut González Cantalapiedra, Esther verfasserin aut Varela, Carmen verfasserin aut García, Ana Belén verfasserin aut Rabal, Obdulia verfasserin aut Oyarzabal, Julen verfasserin (orcid)0000-0003-1941-7255 aut Bischoff, James R. verfasserin aut Klett, Javier verfasserin aut Albarrán, María Isabel verfasserin aut Cebriá, Antonio verfasserin aut Ajenjo, Nuria verfasserin aut García-Serelde, Beatriz verfasserin aut Gómez-Casero, Elena verfasserin aut Cuadrado-Urbano, Manuel verfasserin aut Cebrián, David verfasserin aut Blanco-Aparicio, Carmen verfasserin aut Pastor, Joaquín verfasserin (orcid)0000-0003-0553-8021 aut Enthalten in European journal of medicinal chemistry Amsterdam [u.a.] : Elsevier Science, 1987 168, Seite 87-109 Online-Ressource (DE-627)320443213 (DE-600)2005170-0 (DE-576)25927125X 1768-3254 nnns volume:168 pages:87-109 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 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_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.42 Pharmazeutische Chemie AR 168 87-109 |
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Enthalten in European journal of medicinal chemistry 168, Seite 87-109 volume:168 pages:87-109 |
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Anticancer agents Selective PIM-1/PIM-3 inhibitors pan-PIM inhibitors PIM-1 inhibitors Chemical probes Antiproliferative activity Synergistic effects |
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Martínez-González, Sonia @@aut@@ Rodríguez-Arístegui, Sonsoles @@aut@@ Gómez de la Oliva, Cristina Ana @@aut@@ Hernández, Ana Isabel @@aut@@ González Cantalapiedra, Esther @@aut@@ Varela, Carmen @@aut@@ García, Ana Belén @@aut@@ Rabal, Obdulia @@aut@@ Oyarzabal, Julen @@aut@@ Bischoff, James R. @@aut@@ Klett, Javier @@aut@@ Albarrán, María Isabel @@aut@@ Cebriá, Antonio @@aut@@ Ajenjo, Nuria @@aut@@ García-Serelde, Beatriz @@aut@@ Gómez-Casero, Elena @@aut@@ Cuadrado-Urbano, Manuel @@aut@@ Cebrián, David @@aut@@ Blanco-Aparicio, Carmen @@aut@@ Pastor, Joaquín @@aut@@ |
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2019-01-01T00:00:00Z |
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Martínez-González, Sonia |
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610 DE-600 15,3 ssgn PHARM DE-84 fid 44.42 bkl Discovery of novel triazolo[4,3- Anticancer agents Selective PIM-1/PIM-3 inhibitors pan-PIM inhibitors PIM-1 inhibitors Chemical probes Antiproliferative activity Synergistic effects |
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Discovery of novel triazolo[4,3- |
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Martínez-González, Sonia Rodríguez-Arístegui, Sonsoles Gómez de la Oliva, Cristina Ana Hernández, Ana Isabel González Cantalapiedra, Esther Varela, Carmen García, Ana Belén Rabal, Obdulia Oyarzabal, Julen Bischoff, James R. Klett, Javier Albarrán, María Isabel Cebriá, Antonio Ajenjo, Nuria García-Serelde, Beatriz Gómez-Casero, Elena Cuadrado-Urbano, Manuel Cebrián, David Blanco-Aparicio, Carmen Pastor, Joaquín |
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discovery of novel triazolo[4,3- |
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Discovery of novel triazolo[4,3- |
| abstract |
PIM kinase family (PIM-1, PIM-2 and PIM-3) is an appealing target for the discovery and development of selective inhibitors, useful in various disease conditions in which these proteins are highly expressed, such as cancer. The significant effort put, in the recent years, towards the development of small molecules exhibiting inhibitory activity against this protein family has ended up with several molecules entering clinical trials. As part of our ongoing exploration for potential drug candidates that exhibit affinity towards this protein family, we have generated a novel chemical series of triazolo[4,3-b]pyridazine based tricycles by applying a scaffold hopping strategy over our previously reported potent pan-PIM inhibitor ETP-47453 (compound 2). The structure-activity relationship studies presented herein demonstrate a rather selective PIM-1/PIM-3 biochemical profile for this novel series of tricycles, although pan-PIM and PIM-1 inhibitors have also been identified. Selected examples show significant inhibition of the phosphorylation of BAD protein in a cell-based assay. Moreover, optimized and highly selective compounds, such as 42, did not show significant hERG inhibition at 20 μM concentration, and proved its antiproliferative activity and utility in combination with particular antitumoral agents in several tumor cell lines. |
| abstractGer |
PIM kinase family (PIM-1, PIM-2 and PIM-3) is an appealing target for the discovery and development of selective inhibitors, useful in various disease conditions in which these proteins are highly expressed, such as cancer. The significant effort put, in the recent years, towards the development of small molecules exhibiting inhibitory activity against this protein family has ended up with several molecules entering clinical trials. As part of our ongoing exploration for potential drug candidates that exhibit affinity towards this protein family, we have generated a novel chemical series of triazolo[4,3-b]pyridazine based tricycles by applying a scaffold hopping strategy over our previously reported potent pan-PIM inhibitor ETP-47453 (compound 2). The structure-activity relationship studies presented herein demonstrate a rather selective PIM-1/PIM-3 biochemical profile for this novel series of tricycles, although pan-PIM and PIM-1 inhibitors have also been identified. Selected examples show significant inhibition of the phosphorylation of BAD protein in a cell-based assay. Moreover, optimized and highly selective compounds, such as 42, did not show significant hERG inhibition at 20 μM concentration, and proved its antiproliferative activity and utility in combination with particular antitumoral agents in several tumor cell lines. |
| abstract_unstemmed |
PIM kinase family (PIM-1, PIM-2 and PIM-3) is an appealing target for the discovery and development of selective inhibitors, useful in various disease conditions in which these proteins are highly expressed, such as cancer. The significant effort put, in the recent years, towards the development of small molecules exhibiting inhibitory activity against this protein family has ended up with several molecules entering clinical trials. As part of our ongoing exploration for potential drug candidates that exhibit affinity towards this protein family, we have generated a novel chemical series of triazolo[4,3-b]pyridazine based tricycles by applying a scaffold hopping strategy over our previously reported potent pan-PIM inhibitor ETP-47453 (compound 2). The structure-activity relationship studies presented herein demonstrate a rather selective PIM-1/PIM-3 biochemical profile for this novel series of tricycles, although pan-PIM and PIM-1 inhibitors have also been identified. Selected examples show significant inhibition of the phosphorylation of BAD protein in a cell-based assay. Moreover, optimized and highly selective compounds, such as 42, did not show significant hERG inhibition at 20 μM concentration, and proved its antiproliferative activity and utility in combination with particular antitumoral agents in several tumor cell lines. |
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Rodríguez-Arístegui, Sonsoles Gómez de la Oliva, Cristina Ana Hernández, Ana Isabel González Cantalapiedra, Esther Varela, Carmen García, Ana Belén Rabal, Obdulia Oyarzabal, Julen Bischoff, James R. Klett, Javier Albarrán, María Isabel Cebriá, Antonio Ajenjo, Nuria García-Serelde, Beatriz Gómez-Casero, Elena Cuadrado-Urbano, Manuel Cebrián, David Blanco-Aparicio, Carmen Pastor, Joaquín |
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Rodríguez-Arístegui, Sonsoles Gómez de la Oliva, Cristina Ana Hernández, Ana Isabel González Cantalapiedra, Esther Varela, Carmen García, Ana Belén Rabal, Obdulia Oyarzabal, Julen Bischoff, James R. Klett, Javier Albarrán, María Isabel Cebriá, Antonio Ajenjo, Nuria García-Serelde, Beatriz Gómez-Casero, Elena Cuadrado-Urbano, Manuel Cebrián, David Blanco-Aparicio, Carmen Pastor, Joaquín |
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10.1016/j.ejmech.2019.02.022 |
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