Abstract 7119: Clinic-ready Polθ inhibitor SYX1097 suppresses solid tumors in vivo

Abstract A large fraction of tumors with BRCA1 or BRCA2 mutations only have weak responses to PARP inhibitor (PARPi) treatment, and often develop PARPi resistance. To address these challenges, we have developed SYX1097, a selective and potent oral Polθ inhibitor as a single agent or in combination with PARPi for treating tumors with BRCA mutations. Both Polθ and PARP1 play key roles in microhomology-mediated end joining for DNA double-strand repair and in single-strand DNA gap filling during DNA replication. Using in vitro cellular assays and in vivo animal models, we show that SYX1097 alone or combined with PARPi without obvious side effects. SYX1097 dramatically inhibited proliferation in BRCA -/- isogenic cells with IC50 20 nM, while only had very weak effect on their parental cells (10000nM). SYX1097 also enhanced tumor cell sensitivity to Olaparib 5 to 15 times. SYX1097 in vivo efficacious started at 50mg/kg mono-therapy, and generate 50% tumor regression at 5mg/kg when combined with Olaparib. In a 20-day repeated dosing study, SYX1097 200mg/kg BID was fully tolerated by mice. When considering additive hematological toxicity, comparing with “ATRi + PARPi”, “SYX1097 + PARPi” manifested deep and durable tumor regression without significant body weight loss or reticulocytes decrease. Moreover, SYX1097 is found synthetic lethal with defect of genes not involved in homologous recombination repair and able to suppress tumors with specific gene defect in vivo, which indicated SYX1097 can be used as single agent guided by specific biomarker. SYX1097 has a clean safety profile tested with Safety-Screen 44TM Panel, and is well tolerated in mice, rats and dogs. It possesses remarkable pharmacokinetic properties in various species, with no hematological toxicity observed during the preclinical toxicity studies. SYX1097 is advancing towards IND filing in 2024. Collectively, SYX1097 is a promising small molecule that may be utilized as a single agent or in combination with PARPi for cancer treatment not only limited by HR deficiency. Citation Format: Yilan Zhang, Kai Jiang, Xiaokang Xu, Liu Wu, Chongxun Ge, Yue Xie, Hu He, Song Liu, Xuzhen Tang, Song Shi. Clinic-ready Polθ inhibitor SYX1097 suppresses solid tumors in vivo 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 7119.