Abstract 1647: CC2000199, a potent and selective androgen receptor ligand-directed degrader (AR LDD) with a dual mechanism of action, exhibits anti-tumor activity in multiple enzalutamide-resistant preclinical models for metastatic castration-resista

Abstract The androgen receptor (AR) is a key driver of the cellular processes that contribute to the pathology of prostate cancers at most stages, and drugs that inhibit the activity of this receptor or which interfere with androgen biosynthesis have become the cornerstone of treatments for prostate cancer. Nevertheless, de novo and acquired resistance remains an impediment to a durable clinical response in patients with metastatic castration-resistant prostate cancer (mCRPC), and overcoming resistance to AR pathway inhibitors (ARPIs) has emerged as a major challenge in the treatment of patients with mCRPC. CC2000199 (also called CC-199) is a heterobifunctional ligand-directed degrader (LDD) that enables CRL4CRBN E3 ligase-dependent ubiquitination and degradation of AR and a close analog of BMS-986365. It is a highly potent and selective AR degrader that induces rapid and deep degradation of both wildtype and mutant forms of the receptor. In addition to AR degradation, CC-199 displays AR-inhibitory activity as a direct receptor antagonist with a potency similar to enzalutamide (ENZ) for wildtype AR. The drug is ∼100-fold more potent than ENZ at inhibiting androgen-stimulated transcription of AR target gene FKBP5, and ∼10- to 40-fold more potent than ENZ at inhibiting AR-dependent proliferation of multiple prostate cancer cell lines in vitro. In animal models of advanced prostate cancer, CC-199 demonstrates on-target activity, inducing deep AR degradation, suppressing AR signaling, and inhibiting tumor growth. Indeed, significant tumor volume reductions were achieved by CC-199 in validated models of advanced CRPC and therapy resistant patient-derived xenografts, including those with acquired resistance to ENZ. Collectively, our preclinical data suggest that the AR degrader CC-199 is superior to standard-of-care AR antagonists, such as ENZ, in disease-relevant animal models and ENZ-resistant mCRPC that remain dependent on AR. Citation Format: Surendra Nayak, Massimo Ammirante, Emily Rychak, Debbie Liao, John D. Norris, Suzanne E. Wardell, Shailaja Kasibhatla, Veronique Plantevin-Krenitsky, Evan Horn, Joseph R. Piccotti, Stephen Norris, Raju Kandimalla, Joseph Meiring, Samantha Reiss, Joshua M. Baughman, Marwa Khater, Deborah S. Mortensen, Brian Cathers, Neil Bence, Daniel W. Pierce, Joshua D. Hansen, Lawrence G. Hamann, Donald P. McDonnell, Rama K. Narla, Mark Rolfe, Shuichan Xu. CC2000199, a potent and selective androgen receptor ligand-directed degrader (AR LDD) with a dual mechanism of action, exhibits anti-tumor activity in multiple enzalutamide-resistant preclinical models for metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1647.