Discovery of a potent and selective inhibitor of histone lysine demethylase KDM4D
Histone lysine demethylase 4D (KDM4D) plays an important role in the regulation of tumorigenesis, progression and drug resistance and has been considered a potential target for cancer treatment. However, there is still a lack of potent and selective KDM4D inhibitors. In this investigation, we report...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Fang, Zhen [verfasserIn] Liu, Yang [verfasserIn] Zhang, Rong [verfasserIn] Chen, Qiang [verfasserIn] Wang, Tianqi [verfasserIn] Yang, Wei [verfasserIn] Fan, Yan [verfasserIn] Yu, Chundong [verfasserIn] Xiang, Rong [verfasserIn] Yang, Shengyong [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2021 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: European journal of medicinal chemistry - Amsterdam [u.a.] : Elsevier Science, 1987, 223 |
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| Übergeordnetes Werk: |
volume:223 |
| DOI / URN: |
10.1016/j.ejmech.2021.113662 |
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| Katalog-ID: |
ELV006611974 |
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| 245 | 1 | 0 | |a Discovery of a potent and selective inhibitor of histone lysine demethylase KDM4D |
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| 520 | |a Histone lysine demethylase 4D (KDM4D) plays an important role in the regulation of tumorigenesis, progression and drug resistance and has been considered a potential target for cancer treatment. However, there is still a lack of potent and selective KDM4D inhibitors. In this investigation, we report a new class of KDM4D inhibitors containing the 2-(aryl(pyrrolidine-1-yl)methyl)phenol scaffold, identified through AlphaLisa-based screening, structural optimization, and structure-activity relationship analyses. Among these inhibitors, 24s was the most potent, with an IC50 value of 0.023 ± 0.004 μM. This compound exhibited more than 1500-fold selectivity towards KDM4D versus KDM4A as well as other JMJD subfamily members, indicating good selectivity for KDM4D. Kinetic analysis indicated that 24s did not occupy the 2-oxoglutarate binding pocket. In an in vitro assay, 24s significantly suppressed the proliferation and migration of colorectal cancer (CRC) cells. Overall, this study has identified a good tool compound to explore the biological function of KDM4D and a good lead compound for drug discovery targeting KDM4D. | ||
| 650 | 4 | |a KDM4D | |
| 650 | 4 | |a 2-OG noncompetitive Inhibitor | |
| 650 | 4 | |a Structure-activity relationship | |
| 650 | 4 | |a Epigenetics | |
| 700 | 1 | |a Liu, Yang |e verfasserin |0 (orcid)0000-0002-5071-3928 |4 aut | |
| 700 | 1 | |a Zhang, Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Tianqi |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Chundong |e verfasserin |0 (orcid)0000-0002-4141-8345 |4 aut | |
| 700 | 1 | |a Xiang, Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Shengyong |e verfasserin |0 (orcid)0000-0001-5147-3746 |4 aut | |
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10.1016/j.ejmech.2021.113662 doi (DE-627)ELV006611974 (ELSEVIER)S0223-5234(21)00511-0 DE-627 ger DE-627 rda eng 610 DE-600 15,3 ssgn PHARM DE-84 fid 44.42 bkl Fang, Zhen verfasserin (orcid)0000-0003-4310-7898 aut Discovery of a potent and selective inhibitor of histone lysine demethylase KDM4D 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Histone lysine demethylase 4D (KDM4D) plays an important role in the regulation of tumorigenesis, progression and drug resistance and has been considered a potential target for cancer treatment. However, there is still a lack of potent and selective KDM4D inhibitors. In this investigation, we report a new class of KDM4D inhibitors containing the 2-(aryl(pyrrolidine-1-yl)methyl)phenol scaffold, identified through AlphaLisa-based screening, structural optimization, and structure-activity relationship analyses. Among these inhibitors, 24s was the most potent, with an IC50 value of 0.023 ± 0.004 μM. This compound exhibited more than 1500-fold selectivity towards KDM4D versus KDM4A as well as other JMJD subfamily members, indicating good selectivity for KDM4D. Kinetic analysis indicated that 24s did not occupy the 2-oxoglutarate binding pocket. In an in vitro assay, 24s significantly suppressed the proliferation and migration of colorectal cancer (CRC) cells. Overall, this study has identified a good tool compound to explore the biological function of KDM4D and a good lead compound for drug discovery targeting KDM4D. KDM4D 2-OG noncompetitive Inhibitor Structure-activity relationship Epigenetics Liu, Yang verfasserin (orcid)0000-0002-5071-3928 aut Zhang, Rong verfasserin aut Chen, Qiang verfasserin aut Wang, Tianqi verfasserin aut Yang, Wei verfasserin aut Fan, Yan verfasserin aut Yu, Chundong verfasserin (orcid)0000-0002-4141-8345 aut Xiang, Rong verfasserin aut Yang, Shengyong verfasserin (orcid)0000-0001-5147-3746 aut Enthalten in European journal of medicinal chemistry Amsterdam [u.a.] : Elsevier Science, 1987 223 Online-Ressource (DE-627)320443213 (DE-600)2005170-0 (DE-576)25927125X 1768-3254 nnns volume:223 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 223 |
| spelling |
10.1016/j.ejmech.2021.113662 doi (DE-627)ELV006611974 (ELSEVIER)S0223-5234(21)00511-0 DE-627 ger DE-627 rda eng 610 DE-600 15,3 ssgn PHARM DE-84 fid 44.42 bkl Fang, Zhen verfasserin (orcid)0000-0003-4310-7898 aut Discovery of a potent and selective inhibitor of histone lysine demethylase KDM4D 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Histone lysine demethylase 4D (KDM4D) plays an important role in the regulation of tumorigenesis, progression and drug resistance and has been considered a potential target for cancer treatment. However, there is still a lack of potent and selective KDM4D inhibitors. In this investigation, we report a new class of KDM4D inhibitors containing the 2-(aryl(pyrrolidine-1-yl)methyl)phenol scaffold, identified through AlphaLisa-based screening, structural optimization, and structure-activity relationship analyses. Among these inhibitors, 24s was the most potent, with an IC50 value of 0.023 ± 0.004 μM. This compound exhibited more than 1500-fold selectivity towards KDM4D versus KDM4A as well as other JMJD subfamily members, indicating good selectivity for KDM4D. Kinetic analysis indicated that 24s did not occupy the 2-oxoglutarate binding pocket. In an in vitro assay, 24s significantly suppressed the proliferation and migration of colorectal cancer (CRC) cells. Overall, this study has identified a good tool compound to explore the biological function of KDM4D and a good lead compound for drug discovery targeting KDM4D. KDM4D 2-OG noncompetitive Inhibitor Structure-activity relationship Epigenetics Liu, Yang verfasserin (orcid)0000-0002-5071-3928 aut Zhang, Rong verfasserin aut Chen, Qiang verfasserin aut Wang, Tianqi verfasserin aut Yang, Wei verfasserin aut Fan, Yan verfasserin aut Yu, Chundong verfasserin (orcid)0000-0002-4141-8345 aut Xiang, Rong verfasserin aut Yang, Shengyong verfasserin (orcid)0000-0001-5147-3746 aut Enthalten in European journal of medicinal chemistry Amsterdam [u.a.] : Elsevier Science, 1987 223 Online-Ressource (DE-627)320443213 (DE-600)2005170-0 (DE-576)25927125X 1768-3254 nnns volume:223 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 223 |
| allfields_unstemmed |
10.1016/j.ejmech.2021.113662 doi (DE-627)ELV006611974 (ELSEVIER)S0223-5234(21)00511-0 DE-627 ger DE-627 rda eng 610 DE-600 15,3 ssgn PHARM DE-84 fid 44.42 bkl Fang, Zhen verfasserin (orcid)0000-0003-4310-7898 aut Discovery of a potent and selective inhibitor of histone lysine demethylase KDM4D 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Histone lysine demethylase 4D (KDM4D) plays an important role in the regulation of tumorigenesis, progression and drug resistance and has been considered a potential target for cancer treatment. However, there is still a lack of potent and selective KDM4D inhibitors. In this investigation, we report a new class of KDM4D inhibitors containing the 2-(aryl(pyrrolidine-1-yl)methyl)phenol scaffold, identified through AlphaLisa-based screening, structural optimization, and structure-activity relationship analyses. Among these inhibitors, 24s was the most potent, with an IC50 value of 0.023 ± 0.004 μM. This compound exhibited more than 1500-fold selectivity towards KDM4D versus KDM4A as well as other JMJD subfamily members, indicating good selectivity for KDM4D. Kinetic analysis indicated that 24s did not occupy the 2-oxoglutarate binding pocket. In an in vitro assay, 24s significantly suppressed the proliferation and migration of colorectal cancer (CRC) cells. Overall, this study has identified a good tool compound to explore the biological function of KDM4D and a good lead compound for drug discovery targeting KDM4D. KDM4D 2-OG noncompetitive Inhibitor Structure-activity relationship Epigenetics Liu, Yang verfasserin (orcid)0000-0002-5071-3928 aut Zhang, Rong verfasserin aut Chen, Qiang verfasserin aut Wang, Tianqi verfasserin aut Yang, Wei verfasserin aut Fan, Yan verfasserin aut Yu, Chundong verfasserin (orcid)0000-0002-4141-8345 aut Xiang, Rong verfasserin aut Yang, Shengyong verfasserin (orcid)0000-0001-5147-3746 aut Enthalten in European journal of medicinal chemistry Amsterdam [u.a.] : Elsevier Science, 1987 223 Online-Ressource (DE-627)320443213 (DE-600)2005170-0 (DE-576)25927125X 1768-3254 nnns volume:223 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 223 |
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10.1016/j.ejmech.2021.113662 doi (DE-627)ELV006611974 (ELSEVIER)S0223-5234(21)00511-0 DE-627 ger DE-627 rda eng 610 DE-600 15,3 ssgn PHARM DE-84 fid 44.42 bkl Fang, Zhen verfasserin (orcid)0000-0003-4310-7898 aut Discovery of a potent and selective inhibitor of histone lysine demethylase KDM4D 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Histone lysine demethylase 4D (KDM4D) plays an important role in the regulation of tumorigenesis, progression and drug resistance and has been considered a potential target for cancer treatment. However, there is still a lack of potent and selective KDM4D inhibitors. In this investigation, we report a new class of KDM4D inhibitors containing the 2-(aryl(pyrrolidine-1-yl)methyl)phenol scaffold, identified through AlphaLisa-based screening, structural optimization, and structure-activity relationship analyses. Among these inhibitors, 24s was the most potent, with an IC50 value of 0.023 ± 0.004 μM. This compound exhibited more than 1500-fold selectivity towards KDM4D versus KDM4A as well as other JMJD subfamily members, indicating good selectivity for KDM4D. Kinetic analysis indicated that 24s did not occupy the 2-oxoglutarate binding pocket. In an in vitro assay, 24s significantly suppressed the proliferation and migration of colorectal cancer (CRC) cells. Overall, this study has identified a good tool compound to explore the biological function of KDM4D and a good lead compound for drug discovery targeting KDM4D. KDM4D 2-OG noncompetitive Inhibitor Structure-activity relationship Epigenetics Liu, Yang verfasserin (orcid)0000-0002-5071-3928 aut Zhang, Rong verfasserin aut Chen, Qiang verfasserin aut Wang, Tianqi verfasserin aut Yang, Wei verfasserin aut Fan, Yan verfasserin aut Yu, Chundong verfasserin (orcid)0000-0002-4141-8345 aut Xiang, Rong verfasserin aut Yang, Shengyong verfasserin (orcid)0000-0001-5147-3746 aut Enthalten in European journal of medicinal chemistry Amsterdam [u.a.] : Elsevier Science, 1987 223 Online-Ressource (DE-627)320443213 (DE-600)2005170-0 (DE-576)25927125X 1768-3254 nnns volume:223 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 223 |
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10.1016/j.ejmech.2021.113662 doi (DE-627)ELV006611974 (ELSEVIER)S0223-5234(21)00511-0 DE-627 ger DE-627 rda eng 610 DE-600 15,3 ssgn PHARM DE-84 fid 44.42 bkl Fang, Zhen verfasserin (orcid)0000-0003-4310-7898 aut Discovery of a potent and selective inhibitor of histone lysine demethylase KDM4D 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Histone lysine demethylase 4D (KDM4D) plays an important role in the regulation of tumorigenesis, progression and drug resistance and has been considered a potential target for cancer treatment. However, there is still a lack of potent and selective KDM4D inhibitors. In this investigation, we report a new class of KDM4D inhibitors containing the 2-(aryl(pyrrolidine-1-yl)methyl)phenol scaffold, identified through AlphaLisa-based screening, structural optimization, and structure-activity relationship analyses. Among these inhibitors, 24s was the most potent, with an IC50 value of 0.023 ± 0.004 μM. This compound exhibited more than 1500-fold selectivity towards KDM4D versus KDM4A as well as other JMJD subfamily members, indicating good selectivity for KDM4D. Kinetic analysis indicated that 24s did not occupy the 2-oxoglutarate binding pocket. In an in vitro assay, 24s significantly suppressed the proliferation and migration of colorectal cancer (CRC) cells. Overall, this study has identified a good tool compound to explore the biological function of KDM4D and a good lead compound for drug discovery targeting KDM4D. KDM4D 2-OG noncompetitive Inhibitor Structure-activity relationship Epigenetics Liu, Yang verfasserin (orcid)0000-0002-5071-3928 aut Zhang, Rong verfasserin aut Chen, Qiang verfasserin aut Wang, Tianqi verfasserin aut Yang, Wei verfasserin aut Fan, Yan verfasserin aut Yu, Chundong verfasserin (orcid)0000-0002-4141-8345 aut Xiang, Rong verfasserin aut Yang, Shengyong verfasserin (orcid)0000-0001-5147-3746 aut Enthalten in European journal of medicinal chemistry Amsterdam [u.a.] : Elsevier Science, 1987 223 Online-Ressource (DE-627)320443213 (DE-600)2005170-0 (DE-576)25927125X 1768-3254 nnns volume:223 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 223 |
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Fang, Zhen @@aut@@ Liu, Yang @@aut@@ Zhang, Rong @@aut@@ Chen, Qiang @@aut@@ Wang, Tianqi @@aut@@ Yang, Wei @@aut@@ Fan, Yan @@aut@@ Yu, Chundong @@aut@@ Xiang, Rong @@aut@@ Yang, Shengyong @@aut@@ |
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610 DE-600 15,3 ssgn PHARM DE-84 fid 44.42 bkl Discovery of a potent and selective inhibitor of histone lysine demethylase KDM4D KDM4D 2-OG noncompetitive Inhibitor Structure-activity relationship Epigenetics |
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discovery of a potent and selective inhibitor of histone lysine demethylase kdm4d |
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Discovery of a potent and selective inhibitor of histone lysine demethylase KDM4D |
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Histone lysine demethylase 4D (KDM4D) plays an important role in the regulation of tumorigenesis, progression and drug resistance and has been considered a potential target for cancer treatment. However, there is still a lack of potent and selective KDM4D inhibitors. In this investigation, we report a new class of KDM4D inhibitors containing the 2-(aryl(pyrrolidine-1-yl)methyl)phenol scaffold, identified through AlphaLisa-based screening, structural optimization, and structure-activity relationship analyses. Among these inhibitors, 24s was the most potent, with an IC50 value of 0.023 ± 0.004 μM. This compound exhibited more than 1500-fold selectivity towards KDM4D versus KDM4A as well as other JMJD subfamily members, indicating good selectivity for KDM4D. Kinetic analysis indicated that 24s did not occupy the 2-oxoglutarate binding pocket. In an in vitro assay, 24s significantly suppressed the proliferation and migration of colorectal cancer (CRC) cells. Overall, this study has identified a good tool compound to explore the biological function of KDM4D and a good lead compound for drug discovery targeting KDM4D. |
| abstractGer |
Histone lysine demethylase 4D (KDM4D) plays an important role in the regulation of tumorigenesis, progression and drug resistance and has been considered a potential target for cancer treatment. However, there is still a lack of potent and selective KDM4D inhibitors. In this investigation, we report a new class of KDM4D inhibitors containing the 2-(aryl(pyrrolidine-1-yl)methyl)phenol scaffold, identified through AlphaLisa-based screening, structural optimization, and structure-activity relationship analyses. Among these inhibitors, 24s was the most potent, with an IC50 value of 0.023 ± 0.004 μM. This compound exhibited more than 1500-fold selectivity towards KDM4D versus KDM4A as well as other JMJD subfamily members, indicating good selectivity for KDM4D. Kinetic analysis indicated that 24s did not occupy the 2-oxoglutarate binding pocket. In an in vitro assay, 24s significantly suppressed the proliferation and migration of colorectal cancer (CRC) cells. Overall, this study has identified a good tool compound to explore the biological function of KDM4D and a good lead compound for drug discovery targeting KDM4D. |
| abstract_unstemmed |
Histone lysine demethylase 4D (KDM4D) plays an important role in the regulation of tumorigenesis, progression and drug resistance and has been considered a potential target for cancer treatment. However, there is still a lack of potent and selective KDM4D inhibitors. In this investigation, we report a new class of KDM4D inhibitors containing the 2-(aryl(pyrrolidine-1-yl)methyl)phenol scaffold, identified through AlphaLisa-based screening, structural optimization, and structure-activity relationship analyses. Among these inhibitors, 24s was the most potent, with an IC50 value of 0.023 ± 0.004 μM. This compound exhibited more than 1500-fold selectivity towards KDM4D versus KDM4A as well as other JMJD subfamily members, indicating good selectivity for KDM4D. Kinetic analysis indicated that 24s did not occupy the 2-oxoglutarate binding pocket. In an in vitro assay, 24s significantly suppressed the proliferation and migration of colorectal cancer (CRC) cells. Overall, this study has identified a good tool compound to explore the biological function of KDM4D and a good lead compound for drug discovery targeting KDM4D. |
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| score |
7.3984795 |