Structure-Based Drug Design to Identify Potent, Selective, and Orally Available Cyclin-Dependent Kinase 9 Inhibitors for the Treatment of Castration-Resistant Prostate Cancer

  • J Med Chem. 2026 May 14;69(9):11335-11364. doi: 10.1021/acs.jmedchem.6c00498.
Wenwu Liu  1  2 ,  Limeng Wu  3 ,  Zhuona Rong  1 ,  Limin Zou  1 ,  Yaoguang Huang  4 ,  Wenjie Liu  5 ,  Chao Li  2 ,  Xinhua Liu  6 ,  Kangyao Zhou  1 ,  Kun Hu  1 ,  Jie Huang  7 ,  Chaoyang Chen  1 ,  Qianran Sun  1 ,  Ying Zhou  1 ,  Yi Dong  8 ,  Song Song  1  2 ,  Xiaocong Pang  1  2
Affiliations
  • 1. Department of Pharmacy, Peking University First Hospital, Beijing 100034, PR China.
  • 2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
  • 3. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 4. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 5. College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
  • 6. School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, PR China.
  • 7. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, PR China.
  • 8. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
PMID: 42080481 DOI: 10.1021/acs.jmedchem.6c00498
Abstract

Castration-resistant prostate Cancer (CRPC) progression relies on Androgen Receptor (AR)-driven oncogenic transcription, a process requiring cyclin-dependent kinase 9 (CDK9) as a critical cofactor. In this work, we identified and targeted a distinct subpocket specific to CDK9, leading to the discovery of a series of selective CDK9 inhibitors through structure-based drug design. Compound 91 emerged as a potent and selective CDK9 Inhibitor, demonstrating robust antiproliferative activity against 22Rv1 cells. Mechanistic studies revealed its ability to disrupt Pol II phosphorylation and downregulate short-lived oncoproteins, including AR-V7 and Myc. 91 exhibited favorable pharmacokinetic properties (F = 41%) and significant tumor growth inhibition in CRPC orthotopic models, achieving 66% TGI. This study characterized a distinct subpocket of CDK9 and validated 91 as a promising candidate, paving the way for developing CDK9-targeted therapies to overcome AR dependency in CRPC.

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