Abstract ND04: Discovery of ORIC-944, a novel inhibitor of PRC2 with best-in-class properties for the treatment of prostate cancer

Abstract First generation inhibitors of PRC2 (Polycomb Repressive Complex 2) targeting EZH2 (Enhancer of Zeste Homolog 2) achieved clinical proof-of-concept in follicular lymphoma and epithelioid sarcoma, and emerging clinical data recently revealed promising activity in prostate cancer in combination with AR pathway inhibitors (ARPIs). Here we describe the discovery and development of a second generation PRC2 inhibitor, ORIC-944, a potent, selective, allosteric inhibitor of PRC2 that binds the EED (Embryonic Ectoderm Development) subunit within the complex. Co-crystallization of previously disclosed triazolopyrimidine-based compounds demonstrated binding to EED in the histone H3K27me3 binding pocket, adopting a Lys211-in conformation. We evaluated the apo structure of EED and hypothesized that the Lys211-in conformation may be energetically unfavorable. Using structure-based drug design we pursued a strategy for differentiation of SAR and physicochemical properties by progressing from an early 2-substituted imidazopyrimidine that targets the cryptic pocket with a Lys211-out conformation. Key optimization criteria focused on metabolic stability and solubility, and resulted in the discovery of ORIC-944, an orally bioavailable inhibitor of PRC2 with best-in-class properties. Single agent tumor growth inhibition was observed for ORIC-944 in prostate cancer xenograft models. ORIC-944 also improved ARPI antitumor activity in preclinical combination studies and demonstrated in vitro synergy. Characterization of ORIC-944 revealed superiority to first generation clinical PRC2 inhibitors across a variety of preclinical assessments including potency, solubility, CYP inhibition/induction, PK and oral bioavailability. Together, the preclinical results indicate the desired properties were achieved in ORIC-944 to meet a superior target candidate profile, and the ongoing phase 1b trial (NCT05413421) demonstrates a clinical half-life of approximately 20 hours consistent with once daily dosing and a potential best-in-class profile. Citation Format: Matthew A. Marx, Aaron C. Burns, Nidhi Arora, Thomas P. Bobinski, David M. Briere, Andrew Calinisan, Robin J. Gunn, John M. Ketcham, David Lawson, Matthew Lee, Peter Olson, Christopher R. Smith, Niranjan Sudhakar, James G. Christensen, Chelsea X. Chen, Natalie Yuen, Livia Ulicna, Frank Duong, Christophe Colas, Anjana Ramnath, Ron Xu, Edna Chow Maneval, Pratik S. Multani, Rupal Patel, Archana Kumar, Anneleen Daemen, Anthony Romero, Melissa R. Junttila, Lori S. Friedman. Discovery of ORIC-944, a novel inhibitor of PRC2 with best-in-class properties for the treatment of prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr ND04.