Discovery of JNJ-63576253, a next-generation androgen receptor antagonist active against wild-type and clinically-relevant ligand binding domain mutations in mCRPC

Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Amongst these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of androgen receptor (AR) signaling. In order to address this unmet need, we report the discovery of JNJ-63576253, a next-generation androgen receptor 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 2nd-generation AR targeted therapeutics.