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. 2018 Sep 13;61(17):7710-7728. doi: 10.1021/acs.jmedchem.8b00683.
Masahiro Ito  1 ,  Toshio Tanaka  1 ,  Akinori Toita  1 ,  Noriko Uchiyama  1 ,  Hironori Kokubo  1 ,  Nao Morishita  1 ,  Michael G Klein  2 ,  Hua Zou  2 ,  Morio Murakami  1 ,  Mitsuyo Kondo  1 ,  Tomoya Sameshima  1 ,  Shinsuke Araki  1 ,  Satoshi Endo  1 ,  Tomohiro Kawamoto  1 ,  Gregg B Morin  3  4 ,  Samuel A Aparicio  5 ,  Atsushi Nakanishi  1 ,  Hironobu Maezaki  1 ,  Yasuhiro Imaeda  1
Affiliations
  • 1. Pharmaceutical Research Division , Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome , Fujisawa , Kanagawa 251-8555 , Japan.
  • 2. Department of Structural Biology , Takeda California Inc. , 10410 Science Center Drive , San Diego , California 92121 , United States.
  • 3. Genome Sciences Centre , British Columbia Cancer Agency , 675 West 10th Avenue , Vancouver , British Columbia V5Z 1L3 , Canada.
  • 4. Department of Medical Genetics , University of British Columbia , Vancouver , British Columbia V6H 3N1 , Canada.
  • 5. Department of Molecular Oncology , British Columbia Cancer Agency , 675 West 10th Avenue , Vancouver , British Columbia V5Z 1L3 , Canada.
PMID: 30067358 DOI: 10.1021/acs.jmedchem.8b00683
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.

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