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

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

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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