Abstract P221: Discovery of a covalent inhibitor for an oncogenic mutant RhoAY42C

Abstract Ras homolog family member A (RhoA) is a member of a larger family of Rho proteins of small GTPases, with structural and signaling similarities to Ras proteins. RhoA is involved in multiple cellular processes including cytoskeleton regulation and actin-myosin contractility, etc. Recent studies have shown that the most common RhoA mutation in diffuse gastric cancer (DGC), Y42C, causes a gain-of-function and is associated with the loss of the E-cadherin gene CDH (CDH1). Inhibitors of RhoAY42C could be promising agents for treating DGC that harbors CDH1 mutation/deletion. BridGene expressed RhoAY42C in cells, screened our proprietary covalent library against the RhoAY42C live cells, and employed our chemoproteomic platform IMTACTM (Isobaric Mass Tagged Affinity Characterization) to detect covalent labeling of the mutant RhoA protein. A pilot screening led to the successful identification of a covalent ligand of RhoAY42C, BGS1933. Mass spec analysis has confirmed the covalent modification of Cys42 in RhoA by BGS1933. Dose-dependent binding of BGS1933 to RhoAY42C was measured using an orthogonal fluorescence-based assay. The Cancer Genome Atlas (TCGA) study shows that ~1% DGC patients harbor the oncogenic mutant RhoAY42C. The discovery of a covalent inhibitor of RhoAY42C will enable us to validate the role of RhoAY42C in DGC and facilitate the development of new first-in-class targeted therapies for the treatment of gastric cancer. Citation Format: Shirley Guo, Ping Cao. Discovery of a covalent inhibitor for an oncogenic mutant RhoAY42C [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P221.