Discovery of Potential First-in-Class Dual Ligand-Directed Degrader and Antagonist of the Androgen Receptor: BMS-986365

Journal of Medicinal Chemistry 2026

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Authors: Deborah S. Mortensen, Surendra Nayak, Veronique Plantevin-Krenitsky, Evan J. Horn, Joseph D. Meiring, Samantha Reiss, Kimberly Peacock, Jingjing Zhao, Xiaochu Ba, Stephen Norris, Matthew D. Alexander, Matthew Correa
+29 more Dehua Huang, Jean-François Brazeau, John Sapienza, Lida Tehrani, Mark Nagy, Brandon Whitefield, Patrick Papa, Roy Harris, Virginia Grant, John D. Norris, Massimo Ammirante, Emily Rychak, Suzanne E. Wardell, Toshiya Tsuji, Courtney G. Havens, Ken Liu, Joseph R. Piccotti, Deepak Dalvie, Yang Tang, Nadia Guerrero, Lisa Sapinoso, Joshua M. Baughman, Brian E. Cathers, Mark Rolfe, Lawrence G. Hamann, Donald Patrick McDonnell, Rama Krishna Narla, Joshua D. Hansen, Shuichan Xu
DOI: 10.1021/acs.jmedchem.6c01590
Cited by: 1
References: 18

Abstract

Androgen receptor (AR) signaling is central to the progression of prostate cancer, including castration-resistant disease. Targeted protein degradation, particularly through heterobifunctional compounds, represents a significant advancement in eliminating disease-causing proteins beyond traditional inhibition. Here, we describe the medicinal chemistry discovery of BMS-986365, a novel dual-function AR degrader and an antagonist. BMS-986365 selectively and efficiently degrades both wild-type and clinically relevant mutant ARs while also antagonizing residual AR activity. This dual mechanism results in the robust inhibition of AR-driven pathways and prostate cancer cell growth. The development of BMS-986365 highlights the potential of targeted protein degradation strategies to overcome resistance and improve therapeutic outcomes in prostate cancer.

Fields of Study & Subjects

Prostate Cancer Treatment and Research Estrogen and related hormone effects Hormonal and reproductive studies

Publication details

Journal / source
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Volume
69
Issue
14
Pages
16346–16362
Publication date
10 July 2026
Language
EN