2. Academic Validation
  3. Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader

Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader

  • J Med Chem. 2024 Oct 24;67(20):18247-18264. doi: 10.1021/acs.jmedchem.4c01596.
Licheng Zhou 1 2,  Kaijie Zhou 2 3,  Yu Chang 4 5,  Jianzhang Yang 1,  Bohai Fan 2,  Yuhan Su 2,  Zilu Li 2,  Rahul Mannan 4 5,  Somnath Mahapatra 4 5,  Ming Ding 6,  Fengtao Zhou 1,  Weixue Huang 2,  Xiaomei Ren 2,  Jian Xu 7,  George Xiaoju Wang 4 5 8,  Jinwei Zhang 2,  Zhen Wang 2,  Arul M Chinnaiyan 4 5 8 9 10,  Ke Ding 1 2
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, China.
  • 2 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., Shanghai 200032, China.
  • 3 University of Chinese Academy of Sciences, No. 1 Yanxihu Road, Huairou District, Beijing 101408, China.
  • 4 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 6 School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
  • 7 Livzon Research Institute, Livzon Pharmaceutical Group Inc., No. 38, Chuangye North Road, Jinwan District, Zhuhai 519000, China.
  • 8 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 9 Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 10 Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 39388374 DOI: 10.1021/acs.jmedchem.4c01596
Abstract

Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) emerges as a new potential therapeutic approach for triple-negative breast Cancer (TNBC) and Other human cancers. While several proteolysis-targeting chimera (PROTAC) degraders of CDK12/13 were reported, none are orally bioavailable. Here, we report the discovery of ZLC491 as a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader. The compound effectively degraded CDK12 and CDK13 with DC50 values of 32 and 28 nM, respectively, in TNBC MDA-MB-231 cells. Global proteomic assessment and mechanistic studies revealed that ZLC491 selectively induced CDK12/13 degradation in a cereblon- and proteasome-dependent manner. Furthermore, the molecule efficiently suppressed transcription and expression of long genes, predominantly a subset of genes associated with DNA damage response, and significantly inhibited proliferation of multiple TNBC cell lines. Importantly, ZLC491 achieved an oral bioavailability of 46.8% in rats and demonstrated potent in vivo degradative effects on CDK12/13 in an MDA-MB-231 xenografted mouse model.

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