Discovery of JNJ-63576253: A Clinical Stage Androgen Receptor Antagonist for F877L Mutant and Wild-Type Castration-Resistant Prostate Cancer (mCRPC)
- 20 January 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 64 (2), 909-924
- https://doi.org/10.1021/acs.jmedchem.0c01563
Abstract
Persistent androgen receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound 4 (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with 4. Subsequent lead optimization of 4 led to amelioration of this pathway and nomination of 5 (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).Keywords
This publication has 35 references indexed in Scilit:
- Role of Androgen Receptor in Prostate Cancer: A ReviewThe World Journal of Men's Health, 2019
- Genomic Hallmarks and Structural Variation in Metastatic Prostate CancerCell, 2018
- Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate CancerThe New England Journal of Medicine, 2018
- Apalutamide Treatment and Metastasis-free Survival in Prostate CancerThe New England Journal of Medicine, 2018
- Androgen receptor targeting drugs in castration‐resistant prostate cancer and mechanisms of resistanceClinical Pharmacology & Therapeutics, 2015
- Integrative Clinical Genomics of Advanced Prostate CancerCell, 2015
- AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate CancerThe New England Journal of Medicine, 2014
- A Clinically Relevant Androgen Receptor Mutation Confers Resistance to Second-Generation Antiandrogens Enzalutamide and ARN-509Cancer Discovery, 2013
- Increased Survival with Enzalutamide in Prostate Cancer after ChemotherapyThe New England Journal of Medicine, 2012
- Abiraterone and Increased Survival in Metastatic Prostate CancerThe New England Journal of Medicine, 2011