6CKX
Structure of CDK12/CycK in complex with a small molecule inhibitor N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)acetamide
Summary for 6CKX
| Entry DOI | 10.2210/pdb6ckx/pdb |
| Descriptor | Cyclin-dependent kinase 12, Cyclin-K, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | kinase, transferase, inhibitor, transferase-cell cycle-inhibitor complex, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 145342.32 |
| Authors | Klein, M.G. (deposition date: 2018-03-01, release date: 2018-08-29, Last modification date: 2024-11-06) |
| Primary citation | Ito, M.,Tanaka, T.,Toita, A.,Uchiyama, N.,Kokubo, H.,Morishita, N.,Klein, M.G.,Zou, H.,Murakami, M.,Kondo, M.,Sameshima, T.,Araki, S.,Endo, S.,Kawamoto, T.,Morin, G.B.,Aparicio, S.A.,Nakanishi, A.,Maezaki, H.,Imaeda, Y. 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. J. Med. Chem., 61:7710-7728, 2018 Cited by PubMed 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. PubMed: 30067358DOI: 10.1021/acs.jmedchem.8b00683 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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