Discovery of 3-Benzyl-1-(trans-4-(5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea Derivatives as Novel and Selective Cyclin-Dependent Kinase 12 (CDK12) Inhibitors
Ito, M; Kondo, M; Sameshima, T; Araki, S; Endo, S; Kawamoto, T; Morin, GB; Aparicio, SA; Nakanishi, A; Maezaki, H; Imaeda, Y; Tanaka, T; Toita, A; Uchiyama, N; Kokubo, H; Morishita, Nao; Klein, MG; Zou, Hua; Murakami, M; ,
| HERO ID | 7186559 |
|---|---|
| In Press | No |
| Year | 2018 |
| Title | Discovery of 3-Benzyl-1-(trans-4-(5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea Derivatives as Novel and Selective Cyclin-Dependent Kinase 12 (CDK12) Inhibitors |
| Authors | Ito, M; Kondo, M; Sameshima, T; Araki, S; Endo, S; Kawamoto, T; Morin, GB; Aparicio, SA; Nakanishi, A; Maezaki, H; Imaeda, Y; Tanaka, T; Toita, A; Uchiyama, N; Kokubo, H; Morishita, Nao; Klein, MG; Zou, Hua; Murakami, M; , |
| Journal | Journal of Medicinal Chemistry |
| Volume | 61 |
| Issue | 17 |
| Page Numbers | 7710-7728 |
| Abstract | Cyclin-dependent kinase 12 (CDK12) plays a key role in the coordination of transcription with elongation and mRNA processing. CDK12 mutations found in tumors and CDK12 inhibition sensitize cancer cells to DNA-damaging reagents and DNA-repair inhibitors. This suggests that CDK12 inhibitors are potential therapeutics for cancer that may cause synthetic lethality. Here, we report the discovery of 3-benzyl-1-(trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea derivatives as novel and selective CDK12 inhibitors. Structure-activity relationship studies of a HTS hit, structure-based drug design, and conformation-oriented design using the Cambridge Structural Database afforded the optimized compound 2, which exhibited not only potent CDK12 (and CDK13) inhibitory activity and excellent selectivity but also good physicochemical properties. Furthermore, 2 inhibited the phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II and induced growth inhibition in SK-BR-3 cells. Therefore, 2 represents an excellent chemical probe for functional studies of CDK12 and could be a promising lead compound for drug discovery. |
| Doi | 10.1021/acs.jmedchem.8b00683 |
| Pmid | 30067358 |
| Wosid | WOS:000444921600021 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Scopus URL: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85052400615&doi=10.1021%2facs.jmedchem.8b00683&partnerID=40&md5=009ad55f0e24c714a87feb192e0f8176 |
| Is Public | Yes |
| Language Text | English |
| Keyword | 1 [4 [(5 cyanopyridin 2 yl)amino]cyclohexyl] 3 (cyclohexylmethyl) 1 [4 (1 methyl 1h pyrazol 4 yl)phenyl]urea; 1 [4 [(5 cyanopyridin 2 yl)amino]cyclohexyl] 3 ethyl 1 [4 (1 methyl 1h pyrazol 4 yl)phenyl]urea; 1 [[4 (1 methyl 1h pyrazol 4 yl)phenyl]sulfonyl]piperidin 4 amine; 2 [[1 [[4 (1 methyl 1h pyrazol 4 yl)phenyl]sulfonyl]piperidin 4 yl]amino]isonicotinonitrile; 3 benzyl 1 [4 [(5 cyanopyridin 2 yl)amino]cyclohexyl] 1 arylurea derivative; 3 benzyl 1 [4 [(5 cyanopyridin 2 yl)amino]cyclohexyl] 1 phenylurea; 3 benzyl 1 [4 [(5 cyanopyridin 2 yl)amino]cyclohexyl] 1 [4 (1 methyl 1h pyrazol 4 yl)phenyl]urea; 3 benzyl 1 [4 [(5 cyanopyridin 2 yl)amino]cyclohexyl] 1 [4 (1 methyl 6 oxo 1,6 dihydropyridin 3 yl)phenyl]urea; 4 [[1 [[4 (1 methyl 1h pyrazol 4 yl)phenyl]sulfonyl]piperidin 4 yl]amino]benzonitrile; 5 methoxy n [1 [[4 (1 methyl 1h pyrazol 4 yl)phenyl]sulfonyl]piperidin 4 yl]pyridin 2 amine; 6 (piperidin 4 ylamino)nicotinonitrile; 6 [methyl [1 [[4 (1 methyl 1h pyrazol 4 yl)phenyl]sulfonyl]piperidin 4 yl]amino]nicotinonitrile; 6 [[1 [4 (1 methyl 1h pyrazol 4 yl)benzoyl]piperidin 4 yl]amino]nicotinonitrile; 6 [[1 [4 (1 methyl 1h pyrazol 4 yl)benzyl]piperidin 4 yl]amino]nicotinonitrile; 6 [[1 [[4 (1 methyl 1h pyrazol 4 yl)phenyl]sulfonyl]piperidin 4 yl]amino]nicotinonitrile; 6 [[1 [[4 (1 methyl 1h pyrazol 4 yl)phenyl]sulfonyl]piperidin 4 yl]amino]pyridine 2 carbonitrile; 6 [[4 [[4 (1 methyl 1h pyrazol 4 yl)phenyl]amino]cyclohexyl]amino]nicotinonitrile; benzyl [4 [(5 cyanopyridin 2 yl)amino]cyclohexyl][4 (1 methyl 1h pyrazol 4 yl)phenyl]carbamate; cyclin dependent kinase inhibitor; methyl [4 [(5 cyanopyridin 2 yl)amino]cyclohexyl][4 (1 methyl 1h pyrazol 4 yl)phenyl]carbamate; n [1 [[4 (1 methyl 1h pyrazol 4 yl)phenyl]sulfonyl]piperidin 4 yl] 5 (trifluoromethyl)pyridin 2 amine; n [1 [[4 (1 methyl 1h pyrazol 4 yl)phenyl]sulfonyl]piperidin 4 yl]pyridin 2 amine; n [4 (1 methyl 1h pyrazol 4 yl)phenyl] n [4 (quinazolin 2 ylamino)cyclohexyl]acetamide; n [4 [(5 cyanopyridin 2 yl)amino]cyclohexyl] n [4 (1 methyl 1h pyrazol 4 yl)phenyl] 3 phenylpropanamide; n [4 [(5 cyanopyridin 2 yl)amino]cyclohexyl] n [4 (1 methyl 1h pyrazol 4 yl)phenyl]acetamide; n [4 [(5 cyanopyridin 2 yl)amino]cyclohexyl] n [4 (1 methyl 1h pyrazol 4 yl)phenyl]methanesulfonamide; tert butyl [4 [(4 bromophenyl)amino]cyclohexyl]carbamate; tert butyl [4 [[4 (1 methyl 1h pyrazol 4 yl)phenyl]amino]cyclohexyl]carbamate; unclassified drug; unindexed drug; urea derivative; CDK12 protein, human; cyclin dependent kinase; enzyme inhibitor; RNA polymerase II; antineoplastic activity; Article; carboxy terminal sequence; cell viability; controlled study; drug binding; drug conformation; drug design; drug synthesis; enzyme inhibition; growth inhibition; human; human cell; hydrogen bond; IC50; physical chemistry; protein phosphorylation; RNA processing; SK-BR-3 cell line; structure activity relation; Suzuki reaction; breast tumor; cell survival; chemistry; drug development; enzymology; female; genetics; metabolism; pathology; phosphorylation; tumor cell culture; Breast Neoplasms; Cell Survival; Cyclin-Dependent Kinases; Drug Discovery; Enzyme Inhibitors; Female; Humans; Phosphorylation; RNA Polymerase II; Structure-Activity Relationship; Tumor Cells, Cultured |