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

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.

Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs

“…Preliminary findings from an ongoing Phase 1/2 clinical study are encouraging, showing that ARV-766 is generally well-tolerated and potentially effective. According to a recent study, there is a growing frequency of mutations in the ligandbinding domain of the AR, and the incidence of a specific mutation (L702H) is on the rise [55]. Projections indicate that around 11% of mCRPC cases in 2023 will involve the L702H AR mutation (Table 2).…”

“…Tolerability suitable for mCRPC and mCSPC According to a recent study, there is a growing frequency of mutations in the ligandbinding domain of the AR, and the incidence of a specific mutation (L702H) is on the rise [55]. Projections indicate that around 11% of mCRPC cases in 2023 will involve the L702H AR mutation (Table 2).…”