Abstract 4482: Discovery of GH2616, a potent and selective KIF18A inhibitor with robust in vivo efficacy in p53 mutant cancer

Abstract Chromosomal instability (CIN) is one of the hallmarks of cancer. Cancer cells often undergo whole-genome doubling (WGD) and P53 represents a major barrier to the proliferation of WGD+ cells. Therefore, cancer cells with either CIN or WGD often harbor the p53 mutation. Recently, KIF18A has emerged as a potential therapeutic target in CIN or WGD cancer cells. We have identified a potent and selective KIF18A inhibitor, GH2616. In vitro, GH2616 inhibited the kinesin motor activity with an IC50 less than 50 nM, and with an EC50 less than 50 nM in the mitotic index assay using HT29 cells (WGD). In vivo, GH2616 inhibited the growth of WGD CDX models with a dose dependent manner. GH2616 has good oral bioavailability in different species and metabolic stability for QD dosing. This compound also showed low potential of DDI thus suitable for drug combinations. In a cell panel with more than 200 cell lines, GH2616 selectively inhibit the growth of cells with p53 mutant and some other specific biomarkers in multiple tumor types. In conclusion, we discovered GH2616 as a novel KIF18A inhibitor with potent in vivo efficacy. It is currently under evaluation in IND-enabling studies and IND filing is expected in Q4, 2023. Citation Format: Jie Jack Li, Guiping Zhang, Jiapeng Li. Discovery of GH2616, a potent and selective KIF18A inhibitor with robust in vivo efficacy in p53 mutant cancer. [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 4482.