Discovery of JNJ-63576253, a Next-Generation Androgen Receptor Antagonist Active Against Wild-Type and Clinically Relevant Ligand Binding Domain Mutations in Metastatic Castration-Resistant Prostate Cancer.

Jonathan R Branch,Yolanda T Chong,Tammy L Bush,Georges Habineza,Christopher J Parrett,Peter J Connolly,Kathryn Packman,Zhuming Zhang,Marco M Gottardis,Ian Hickson,Gilles Bignan,Lieven Meerpoel,Janine Ondrus,James R Bischoff,Geert Van Hecke,Vineet Pande,Steffen Jaensch

doi:10.1158/1535-7163.mct-20-0510

Abstract

Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor (AR) pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Among these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of AR signaling. To address this unmet need, we report the discovery of JNJ-63576253, a next-generation AR pathway inhibitor that potently abrogates AR signaling in models of human prostate adenocarcinoma. JNJ-63576253 is advancing as a clinical candidate with potential effectiveness in the subset of patients who do not respond to or are progressing while on second-generation AR-targeted therapeutics.

Highlights

An estimated 31,620 men died from prostate cancer in 2019, representing 10% of all cancer-related deaths [1]
Utilizing molecular docking models informed by published data for other nuclear receptors, we confirmed that mutation from phenylalanine to leucine at androgen receptor (AR) amino acid 877 reduces steric hindrance in the ligand binding pocket
Despite therapeutic advances in the past decade, an estimated 31,620 men died from prostate cancer in the United States in 2019 [1], representing a significant unmet need

Summary

Introduction

An estimated 31,620 men died from prostate cancer in 2019, representing 10% of all cancer-related deaths [1]. Over the past 20 years, mortality has decreased nearly 50% [1], partly attributable to the development of androgen receptor (AR) pathway inhibitor therapy, abiraterone acetate plus prednisone Patient progression while on these therapies has been associated with numerous resistance mechanisms. These include mutations specific to the AR signaling pathway (AR aberrations): gene [5, 6] or enhancer [7] amplification, genomic structural rearrangement [8], splice variant isoform expression [9], ligand binding domain (LBD) point mutations [10, 11], adrenal and intraprostatic androgen synthesis [12,13,14], and glucocorticoid receptor bypass [15, 16]. Treatment-emergent small-cell neuroendocrine [17] and double-negative [18] prostate cancer, in which prostate lineage specificity is lost in response to AR pathway inhibition, have

Methods

Results

Conclusion