Abstract 482: Discovery of a novel and oral CHK1 inhibitor for the treatment of solid tumors
Authors: Gao Xin , Liao Yonggang , Li Qi , Yang Ling , Zhao Chunyan , Teng Yanfen , Liu Lei , Qian Wenyuan , Yu Xiaohong 
Published: April 2023

Abstract
Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR), a complex network of genes responsible for sensing and responding to specific types of DNA damage, in which numerous interdependent signaling pathways and machineries are involved. Although deficiencies in these responses promote cancer initiation and progression via accumulated mutations, they also provide targetable vulnerabilities relatively specific to cancer cells that can be exploited with the use of DDR inhibitors. The cell cycle checkpoint kinases CHK1 and CHK2 are prime targets of DDR inhibitors, working with the key upstream regulators of the DDR signaling cascade, ATR and ATM, respectively, to halt cell cycle progression and initiate DNA repair via distinct but overlapping pathways. CHK1 and/or CHK2 inhibitors have been developed in the past. However, many of them were discontinued before making to phase III clinical trials, in most cases owing to severe side effects induced by their non-specific nature. Others are related to their limited clinical efficacy, such as SRA737 which selectively inhibits CHK1 but not CHK2. Prexasertib (LY2606368), one of the few agents to undergo clinical trials, specifically inhibits both CHK1 and CHK2, displaying obvious therapeutic effects but also raising inevitable target-associated drug toxicities and a potential compliance issue due to intravenous administration. Given the fact that CHK2 aids in the coordination with CHK1 pathway, adjustment in the intensity of inhibition to both kinases could provide a suitable balance between efficacy and toxicity. Here, we describe the characterization of XS-02, a novel and orally bioavailable CHK1 inhibitor with moderate potency against CHK2, which shows manageable side effects and broad antitumor activity in various solid tumors, including tumors resistant to PARP inhibitors. XS-02 specifically inhibited both CHK1 and CHK2 kinases in different degree with IC50 values of 2 and 282 nM, respectively. In vitro western blotting assays demonstrated that XS-02 decreased phosphorylation of CHK1 completely but partially for CHK2 in OVCAR3 cancer cells. Its potency against proliferation of cells with low nM IC50 was exhibited in multiple cancer cell lines instead of normal cells. Oral dosing of XS-02 as a single agent induced dose-dependent tumor growth inhibition of OVCAR3 and MD-MBA-436 xenografts. Moreover, the combination of XS-02 and olaparib, a PARP inhibitor, accelerated tumor regression, which synergy was confirmed in a patient-derived tumor xenograft animal model of acquired resistance to olaparib, without significant body weight changes. In vivo assays showed that XS-02 was generally well tolerated with an acceptable oral bioavailability across multiple non-clinical species. These results support the agent as a clinical candidate for the treatment of solid tumors. An Investigational New Drug application is planned for 2023.
Citation Format: Xin Gao, Yonggang Liao, Qi Li, Ling Yang, Chunyan Zhao, Yanfen Teng, Lei Liu, Wenyuan Qian, Xiaohong Yu. Discovery of a novel and oral CHK1 inhibitor for the treatment of solid tumors [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 482.