2. Academic Validation
  3. Small-Molecule Inhibition of Androgen Receptor Dimerization as a Strategy against Prostate Cancer

Small-Molecule Inhibition of Androgen Receptor Dimerization as a Strategy against Prostate Cancer

  • ACS Cent Sci. 2023 Mar 8;9(4):675-684. doi: 10.1021/acscentsci.2c01548.
Weitao Fu 1 2,  Hao Yang 3,  Chenxian Hu 1 4,  Jianing Liao 1,  Zhou Gong 5,  Minkui Zhang 1,  Shuai Yang 5 6,  Shangxiang Ye 7,  Yixuan Lei 1,  Rong Sheng 1 8,  Zhiguo Zhang 3 9,  Xiaojun Yao 10,  Chun Tang 11,  Dan Li 1 8,  Tingjun Hou 1
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 2 Department of Computer-Aided Drug Design, Jiangsu Vcare PharmaTech Co. Ltd., Nanjing 211800, China.
  • 3 Institute of Zhejiang University - Quzhou, Zhejiang University, Quzhou 324000, Zhejiang, China.
  • 4 Polytechnic Institute, Zhejiang University, Hangzhou 310015, Zhejiang, China.
  • 5 Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, Hubei, China.
  • 6 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 7 Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, Hubei, China.
  • 8 Jinhua Institute of Zhejiang University, Jinhua 321000, Zhejiang, China.
  • 9 Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, Zhejiang, China.
  • 10 Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China.
  • 11 Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, and Center for Quantitate Biology, PKU-Tsinghua Center for Life Science, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
PMID: 37122451 DOI: 10.1021/acscentsci.2c01548
Abstract

The clinically used Androgen Receptor (AR) antagonists for the treatment of prostate Cancer (PCa) are all targeting the AR ligand binding pocket (LBP), resulting in various drug-resistant problems. Therefore, a new strategy to combat PCa is urgently needed. Enlightened by the gain-of-function mutations of androgen insensitivity syndrome, we discovered for the first time small-molecule antagonists toward a prospective pocket on the AR dimer interface named the dimer interface pocket (DIP) via molecular dynamics (MD) simulation, structure-based virtual screening, structure-activity relationship exploration, and bioassays. The first-in-class antagonist M17-B15 targeting the DIP is capable of effectively disrupting AR self-association, thereby suppressing AR signaling. Furthermore, M17-B15 exhibits extraordinary anti-PCa efficacy in vitro and also in mouse xenograft tumor models, demonstrating that AR dimerization disruption by small molecules targeting the DIP is a novel and valid strategy against PCa.

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