2. Academic Validation
  3. Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13

Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13

  • J Med Chem. 2022 Aug 25;65(16):11066-11083. doi: 10.1021/acs.jmedchem.2c00384.
Jianzhang Yang 1,  Yu Chang 1 2,  Jean Ching-Yi Tien 2 3,  Zhen Wang 4,  Yang Zhou 1,  Pujuan Zhang 4,  Weixue Huang 4,  Josh Vo 2,  Ingrid J Apel 2,  Cynthia Wang 2,  Victoria Zhixuan Zeng 2,  Yunhui Cheng 2,  Shuqin Li 2,  George Xiaoju Wang 2 3 5,  Arul M Chinnaiyan 2 3 5 6 7,  Ke Ding 1 4 8 9
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou 511400, People's Republic of China.
  • 2 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Ling Ling Road, Shanghai 200032, People's Republic of China.
  • 5 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 6 Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 7 Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 8 Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, People's Republic of China.
  • 9 The First Affiliated Hospital (Huaqiao Hospital), Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
PMID: 35938508 DOI: 10.1021/acs.jmedchem.2c00384
Abstract

Selective degradation of the cyclin-dependent kinases 12 and 13 (CDK12/13) presents a novel therapeutic opportunity for triple-negative breast Cancer (TNBC), but there is still a lack of dual CDK12/13 degraders. Here, we report the discovery of the first series of highly potent and selective dual CDK12/13 degraders by employing the proteolysis-targeting chimera (PROTAC) technology. The optimal compound 7f effectively degraded CDK12 and CDK13 with DC50 values of 2.2 and 2.1 nM, respectively, in MDA-MB-231 breast Cancer cells. Global proteomic profiling demonstrated the target selectivity of 7f. In vitro, 7f suppressed expression of core DNA damage response (DDR) genes in a time- and dose-dependent manner. Further, 7f markedly inhibited proliferation of multiple TNBC cell lines including MFM223, with an IC50 value of 47 nM. Importantly, 7f displayed a significantly improved antiproliferative activity compared to the structurally similar inhibitor 4, suggesting the potential advantage of a CDK12/13 degrader for TNBC targeted therapy.

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