Abstract B058: Development of a potent and selective orally available AVPR1A antagonist for castration resistant prostate cancer

Abstract Treatment options for castration resistant prostate cancer (CRPC) reduce quality of life and modestly extend overall survival. We previously showed that the GPCR arginine vasopressin receptor 1A (AVPR1A) is overexpressed in advanced PC and drives CRPC. In preclinical xenograft models, relcovaptan, an orally available AVPR1A antagonist, decreased growth of newly emergent, established and end-stage bone CRPC (Zhao et al. Sci Transl Med 2019, Heidman et al. Mol Cancer Res 2022). Unfortunately, there are no FDA-approved AVPR1A-selective antagonists. Although relcovaptan and the more recently developed balovaptan were proven safe in human clinical trials for non-cancer disorders, these antagonists are no longer available for clinical studies. To advance our findings toward clinical application, we report here the development and characterization of a series of seven novel AVPR1A antagonists based on the chemical structure of balovaptan (Schnider et al. J. Med. Chem. 2020). Compounds were evaluated for efficacy and selectivity using the BRET-based TRUPATH platform (Olsen et al. Nat Chem Biol 2020), which measures dissociation of the heterotrimeric G protein complex, an early event in GPCR signaling. From these studies, UMF-504 was selected as our lead compound. This compound showed high potency (IC50 1.4x10-8M) and high selectivity for AVPR1A among the AVPR family and the closely related oxytocin receptor. In CRPC cells, UMF-504 decreased AVP-induced intracellular calcium release, pERK and pSTAT3. This was also observed in explant cultures generated from AVPR1A-expressing LuCaP PDXs. UMF-504 decreased proliferation of CRPC but not androgen-dependent PC nor non-tumorigenic prostate epithelial cell lines. UMF-504 has excellent in vitro and in vivo DMPK (oral administration) with superior bioavailability in common PC metastatic tissues including bone. Orally administered UMF-504 decreased castration resistant C4-2B and VCaP-CR subcutaneous tumor establishment in castrated mice. Reduced tumor establishment was similar to the clinically used AR antagonist enzalutamide. In a C4-2B xenograft model of castration-resistant progression, UMF-504 decreased tumor volume, as well as markers of tumor progression. Unsurprisingly based on clinical trials with vaptan-type AVPR1A antagonists, neither animal weights nor behavior were affected by UMF-504. Our results show that UMF-504 is an orally available, potent and selective antagonist for AVPR1A with demonstrable safety and promise for CRPC therapy. Citation Format: Nahuel Peinetti, Morgan V. Pantone, Kyutae Lee, Maria J. Martinez, Benjamin Pomeroy, Eva Corey, Mariana Cooke, Marcelo G. Kazanietz, Daniel G. Isom, Yangbo Feng, Kerry L. Burnstein. Development of a potent and selective orally available AVPR1A antagonist for castration resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B058.