Antitumor activity of JNJ-63576253 (TRC253), a small molecule antagonist of F877L mutant and wild-type androgen receptor

Androgen receptor (AR) antagonists have transformed prostate cancer patient care by targeting a key nodal point in tumor cell signaling. However, despite the impressive clinical activity of first- and second-generation antiandrogens, acquired resistance frequently emerges. Point mutations in the ligand-binding domain of AR, such as phenylalanine to leucine at position 877 (ARF877L), account for 10-20% of resistance. Such mutations are characterized by receptor activation, rather than inhibition, by first- and second-generation antiandrogen therapeutics. JNJ-63576253 is a potent, high affinity competitive binder of wild type and mutant AR, including F877L. JNJ-63576253 blocks AR nuclear translocation, AR binding to DNA, and AR-dependent transcription. JNJ-63576253 inhibits the proliferation of androgen receptor driven prostate cancer cell lines, including those bearing ARF877L. In the Hershberger assay in male Sprague Dawley rats, oral administration of JNJ-63576253 inhibited androgen sensitive organ (ASO) development in a dose-dependent manner. In male SHO mice bearing LNCaP xenografts with either wild-type or ARF877L, daily treatment with 30 mg/kg JNJ-63576253 treatment resulted in statistically significant antitumor activity, whereas second-generation antiandrogen enzalutamide had no antitumor efficacy in the LNCaP ARF877L mutant model. Janssen and Tracon Pharma have entered a strategic licensing collaboration, whereby Tracon possesses exclusive rights for clinical development of JNJ-63576253 (now called TRC253). Tracon has entered TRC253 into Ph1/2A clinical evaluation in metastatic castration-resistant prostate cancer patients. Citation Format: Tammy L. Bush, Georges Habineza Ndikuyeze, Gilles Bignan, Jonathan Branch, Janine Ondrus, Yifan Shi, Leopoldo Luistro, James Hastings, Joseph Erhardt, Ian Hickson, Shefali Patel, Peter Connolly, Zhuming Zhang, James Bischoff, Brent Rupnow, Marco Gottardis, Kathryn Packman. Antitumor activity of JNJ-63576253 (TRC253), a small molecule antagonist of F877L mutant and wild-type androgen receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2179.