Abstract 7147: ASN-3186 is a potent and selective inhibitor of USP1 for the treatment of BRCA1/2 mut and HRD+ cancers

Abstract Ubiquitin-specific protease 1 (USP1), a well-characterized member of the deubiquitinating enzyme family, selectively cleaves ubiquitin from various target proteins, including DNA repair protein PCNA. USP1 contributes to oncogenesis by playing critical roles in DNA damage repair processes including translesion synthesis and the Fanconi anemia pathway. Despite the clinical benefit achieved with PARP inhibitors (PARPi) in BRCA-mutated (BRCAm) or homologous recombination deficient (HRD+) populations, some patients either do not respond to therapy or develop resistance. USP1 inhibitors may have the potential to address this unmet clinical need as USP1 functions in distinct DNA damage repair pathway as compared to PARP. ASN-3186 is a novel, potent, and selective USP1 inhibitor with enzyme IC50 value of single digit nanomolar and selectivity 1000-fold against other family members. ASN-3186 demonstrated potent anti-proliferative activity in the BRCA1m triple negative breast cancer (TNBC) cell line, MDA-MB-436 (IC50 30 nM). MDA-MB-436 CDX mouse model confirmed dose-dependent, single-agent inhibitory activity of ASN-3186 in vivo with higher potency than KSQ4279, possibly due to ASN-3186’s higher oral bioavailability. Efficacy is consistent with increase of pharmacodynamic biomarker ub-PCNA. The combination of ASN-3186 and PARPi Olaparib yielded a more robust and durable anti-tumor response, with near-complete tumor regression demonstrated at higher combination dose. Moreover, addition of ASN-3186 significantly sensitized Olaparib’s minimal anti-tumor activity in CAOV3 (ovarian, HRD high) and MX-1 (TNBC, BCRA1/2 mut) models, which are resistant to PAPRi, indicating that it has the potential to overcome PARPi resistance. Synthetic lethal activity was also observed when ASN-3186 was combined with DNA damage drug Gemcitabine. Furthermore, ASN-3186 displayed desirable ADME and PK profiles with high oral bioavailabilities (75%) across species. These data support further clinical development of ASN-3186 as a potential best-in-class USP1 inhibitor, both as a single agent as well as in combination with PARPi, for treatment of BRCA1/2 mut and HRD+ cancers. Citation Format: Qiaoling Sun, Yunfei Chen, Maojiang Wu, Jing Lv, Hongyue Jin, Peng Zeng, Xia Song, Wenfeng Hou, Qi Huang, Wei Niu, Mengyao Zhang, Tie-Lin Wang, Alice Chen. ASN-3186 is a potent and selective inhibitor of USP1 for the treatment of BRCA1/2 mut and HRD+ cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 7147.