Abstract C044: Discovery and characterization of novel fragment binders of the VHR phosphatase as a drug target for cervix cancer

Abstract

Abstract The dual-specificity phosphatase 3 (DUSP3), also known as Vaccinia H1-related phosphatase (VHR) was reported to exhibit elevated protein level in cervix cancer cell lines compared to normal keratinocytes implicating VHR as a novel target for cervical cancer therapeutic. VHR belongs to the superfamily of protein tyrosine phosphatases (PTPs), a large class of human enzymes that is notoriously difficult to target with small molecules. Recent studies have demonstrated some PTP functions as oncogenes to promote tumor development including SHP2 (PTPN11), PTP1B (PTPN1), and VHR (DUSP3). Fragment-based drug discovery (FBDD) has merged as an effective strategy to provide potent ligands, particularly for challenging drug targets such as PTPs. In this study, we present an NMR-based discovery platform designed to discovery fragment hits that exhibit binding affinity to VHR. Our platform employed fluorine NMR, a robust ligand-observed NMR method, to screen fragment library. Subsequent validation of confirmed hits was accomplished through a series of biophysical and biochemical experiments. Structural study such as X-ray crystallography provide binding mode of action of potent molecules with the VHR protein. Using this platform, we have successfully identified several potent fragments that displayed relative selectivity for VHR. Furthermore, We discovered novel ligand binding sites distinguished from the active site. Initial structure-activity relationship (SAR) studies were also conducted, enabling us to explore a set of validated fragment hits that serve as starting point for medicinal chemistry optimization. Moreover, our fragment discovery platform is a promising strategy for discovering potent and selective fragments targeting other PTPs, thereby offering potential therapeutic options for a boarder spectrum of cancer types. Citation Format: Jiaqian WU, Marek R Baranowski, Nicholas D.P. Cosford, Lutz Tautz. Discovery and characterization of novel fragment binders of the VHR phosphatase as a drug target for cervix cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C044.