Discovery of BMS-986365, a First-in-Class Dual Androgen Receptor Ligand-Directed Degrader and Antagonist - for the Treatment of Advanced Prostate Cancer

Sep 29, 2026

Uploaded by Rhys

Discovery and evaluation of BMS-986365 for advanced prostate cancer focuses on a heterobifunctional androgen receptor (AR) ligand-directed degrader designed as a potent cereblon-dependent degrader and competitive AR antagonist to address resistance to AR pathway inhibition. In vitro studies examined AR degradation effects on AR activity and prostate cancer cell proliferation, including intrinsic agonistic versus antagonistic behavior. In vivo, antitumor activity was compared with enzalutamide across cell-line and patient-derived models, showing potent, selective AR degradation and meaningful PSA reduction in metastatic CRPC after ARPI.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Purpose

Experimental Design

Results

Conclusions

Introduction

Discovery of BMS-986365, a First-in-Class Dual Androgen Receptor Ligand-Directed Degrader and Antagonist, for the Treatment of Advanced Prostate Cancer Surendra Nayak1, John D. Norris2, Massimo Ammirante1, Emily Rychak1, Suzanne E. Wardell2, Debbie Liao1, Brandon Toyama1, Raju Kandimalla1, Andy Christoforou1, Toshiya Tsuji1, Ken Liu1, Minerva Tran1, Joseph Meiring1, Samantha Reiss1, Joseph R. Piccotti1, Joshua M. Baughman1, Celia Fontanillo1, Marwa Khater1, Deborah S. Mortensen1, Brian Cathers1, Neil Bence1, Daniel W. Pierce1, Veronique Plantevin-Krenitsky1, Dana Rathkopf3, Joshua D. Hansen1, Lawrence G. Hamann1, Rama Krishna Narla1, Vivek K. Arora1, Donald P. McDonnell2, Mark Rolfe1, and Shuichan Xu1 | | | A | | B | S | | T | R | | A | | C | T | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Purpose: BMS-986365, a heterobifunctional androgen receptor (AR) ligand-directed degrader, was designed as a potent cereblon-dependent degrader and competitive antagonist of the AR to overcome resistance to AR pathway inhibition (ARPI) in metastatic prostate cancer.
Experimental Design: The in vitro impact of BMS-986365– induced AR degradation on AR activity and prostate cancer cell proliferation was evaluated. Intrinsic agonistic and antagonist activities of BMS-986365 were assessed. The in vivo antitumor activity of BMS-986365 was compared with enzalutamide in multiple cell line– or patient-derived prostate cancer models.
Results: BMS-986365 is a potent, rapid, and selective degrader of AR wild-type (WT) and most of the clinically relevant mutants. Degradation of both WT and mutant AR is the key driver of BMS-986365 efficacy, with additional antagonism of residual AR activity enabled through occupancy of its ligand-binding domain. Compared with enzalutamide, BMS- 986365 more efficiently inhibits AR target gene transcription
􀀶 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | and AR-dependent proliferation of prostate cancer cell lines. Whereas enzalutamide increased AR protein in metastatic castration-resistant prostate cancer (CRPC) models, BMS- 986365 maintained low levels of AR protein despite increased AR transcript levels. In vivo, BMS-986365 demonstrated ontarget activity, degrading AR, suppressing AR signaling, and inhibiting growth in validated cell line– and patient-derived xenograft models of castration-sensitive prostate cancer and advanced and/or therapy-resistant CRPC. Clinically, BMS- 986365 reduced PSA in patients with metastatic CRPC after ARPI, including patients with WT AR.
Conclusions: The preclinical observations, coupled with clinical data, strongly support the potential for BMS-986365 to overcome ARPI-resistant disease regardless of AR mutational status. These findings establish BMS-986365 as a first-in-class dual AR degrader and competitive antagonist, likely to emerge asan important tool in the armamentarium to treat prostate cancer. See related commentary by Nyquist and Nelson, p. 13 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |

FAQs

What is BMS-986365 designed to do in prostate cancer?

BMS-986365 is a heterobifunctional androgen receptor (AR) ligand-directed degrader intended to act as a potent cereblon-dependent degrader and competitive antagonist of AR to counter resistance to AR pathway inhibition.

How was BMS-986365 evaluated in the study?

The study assessed in vitro effects of BMS-986365–induced AR degradation on AR activity and prostate cancer cell proliferation, and examined intrinsic agonistic and antagonistic activities. In vivo antitumor activity was compared with enzalutamide across multiple models, including patient-derived xenografts.

What were the key efficacy findings for BMS-986365 compared with enzalutamide?

BMS-986365 showed potent, rapid, and selective degradation of AR wild-type and clinically relevant mutants, suppressing AR signaling and inhibiting growth. Compared with enzalutamide, it more efficiently inhibited AR target gene transcription and maintained low AR protein levels despite increased AR transcripts.

Sep 29, 2026

Uploaded by Rhys