Abstract 502: ISM3091, a novel selective USP1 inhibitor as a targeted anticancer therapy

Abstract Ubiquitin-specific protease 1 (USP1), a well-characterized member of the deubiquitinating enzymes family, cleaves ubiquitin from various target proteins. USP-1 expression is dysregulated in many cancers where it acts as an oncogenic driver with roles in various DNA damage repair processes including translesion synthesis and the Fanconi anemia pathway. Previous data show that USP1 plays a critical role in protecting the replication fork in BRCA1-deficient cells and that its loss results in reduced cell survival and replication fork degradation, suggesting that USP1 inhibitors may be particularly useful in BRCA-deficient tumors. Though PARP inhibitors (PARPi) have shown clinical benefit in BRCA-mutated (BRCAm) populations, some patients either do not respond to therapy or develop resistance. USP1 inhibitors may have the potential to address this unmet clinical need. We evaluated ISM3091, a novel and selective USP1 inhibitor, against tumor cell lines and in vivo models with BRCAm and other homologous recombination repair deficiency (HRD), as well as in homologous recombination (HR)-proficient models.ISM3091 demonstrated potent anti-proliferation activity (IC50, 20 nM) in the BRCA1m triple negative breast cancer (TNBC) cell line, MDA-MB-436, with a ~1500-fold selectivity for BRCAm vs BRCA WT. Synthetic lethality between USP1 and HRD was due to persistent monoubiquitinated PCNA. In vitro data revealed that the combination of ISM3091 and olaparib, a PARPi, had synergistic activity in cell lines with HRD. Multiple in vivo CDX and PDX models confirmed the dose-dependent, single-agent inhibitory activity of ISM3091, with Tumor Growth Inhibition (TGI) of 66% at 30 mg/kg BID (TNBC) and 60% at 50 mg/kg BID (ovarian). The combination of ISM3091 and olaparib yielded a more robust and durable anti-tumor response, even at low doses of ISM3091, with TGI of 91% (TNBC; ISM3091, 3 mg/kg BID + olaparib, 50 mg/kg QD) and 110% (ovarian; ISM3091, 50 mg/kg BID + olaparib, 50 mg/kg QD). Notably, ISM3091 displayed strong single-agent activity (TGI 72% at 50 mg/kg BID) in an ovarian PDX model with acquired resistance to olaparib (BRCA WT), indicating that it has the potential to treat tumors with HRD beyond BRCAm, and also to overcome PARPi resistance. In vivo evaluation against the HR-proficient lung adenocarcinoma cell line, NCIH1792, showed potent efficacy (TGI 86% at 30 mg/kg BID) suggesting a broader ISM3091 potential. ISM3091also displayed very favorable ADME properties and PK profiles, and GLP toxicology studies indicated that it was well tolerated without significant gastrointestinal toxicity or hematological toxicity. These data support the future clinical development of ISM3091 as a potential best-in-class USP1 inhibitor not only for PARPi-resistant/responsive HRD-mutant cancers, both, as a single agent as well as in combination with PARPi, but also for subsets of HR-proficient cancers. Citation Format: Yangguang Li, Jianping Wu, Jinxin Liu, Luoheng Qin, Xin Cai, Junwen Qiao, Ling Wang, Sujata Rao, Feng Ren, Alex Zhavoronkov. ISM3091, a novel selective USP1 inhibitor as a targeted anticancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 502.