Abstract 1749: Discovery of MOMA-313, a potent and selective inhibitor of the Polθ DNA helicase domain for the treatment of HR-deficient tumors

Abstract Loss of homologous recombination (HR), a core DNA damage repair pathway, is common in many types of cancer that are caused by inactivating mutations in BRCA1, BRCA2 and functionally related proteins. HR-deficient tumors are widely treated with PARP inhibitors, but the duration of response and survival benefit is often limited by tolerability issues and by the emergence of clinical resistance mediated by secondary mutations that restore HR activity. MOMA-313 is a novel, potent and selective small molecule inhibitor of DNA polymerase theta (Polθ) in development with a PARP inhibitor to drive deeper and more durable responses in HR-deficient tumors. Polθ is a DNA repair enzyme composed of both a helicase and a polymerase domain that work in tandem to repair DSBs through a process called theta-mediated end-joining (TMEJ). Polθ functions as a back-up DNA repair pathway in most contexts, and genetic ablation of Polθ is well-tolerated in mouse models and in HR-proficient cell lines. However, when HR is disabled, cells rely heavily on Polθ activity for DSB repair. Loss of Polθ activity may also prevent the emergence of clinical PARP inhibitor resistance caused by BRCA reversion mutations which have been linked to Polθ DNA repair activity. MOMA-313 is an inhibitor of the Polθ helicase domain that inhibits cellular TMEJ activity in vitro and in vivo with single-digit nM potency. MOMA-313 synergizes with PARP inhibitors against HR-deficient cell lines in vitro, with no combination impact on HR-proficient cells. Low doses of MOMA-313 drive the regression of HR-deficient tumor xenografts when combined with the PARP inhibitor olaparib, including in models with limited response to olaparib alone. A PK/PD/efficacy relationship directly links exposures required for tumor regressions to target inhibition, as determined by measuring TMEJ inhibition within tumor xenografts. Mechanistically, cryo-EM studies demonstrate MOMA-313 binds to the DNA channel, preventing DNA translocation and synapse formation between opposing ends of the broken DNA. By inhibiting the first of the two sequential Polθ DNA repair activities, MOMA-313 likely prevents the engagement of either Polθ functional domain. MOMA-313 has been optimized to achieve high target coverage at a low human dose, a strong safety profile, and broad combinability especially with PARP inhibitors, where mechanistic synergy may drive deeper responses and prevent clinical resistance in HR-deficient tumors. Clinical evaluation of MOMA-313 is ongoing (NCT06545942), with monotherapy and PARP inhibitor combination arms. Citation Format: Jordan A. Krall, Michael Reutershan, Vinny Motwani, Kelly McGlynn, Yonghong Bai, Christopher Quinn, Manaswni Dhingra, Cen Gao, David Waller, Salah Nabhan, Marc Ballas, Timothy Guzi, Peter Hammerman, Erica Evans. Discovery of MOMA-313, a potent and selective inhibitor of the Polθ DNA helicase domain for the treatment of HR-deficient tumors [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 1749.