GSK2643943A

GSK2643943A is a selective, cell-penetrant small molecule inhibitor of the deubiquitinating enzyme (DUB) ubiquitin-specific peptidase 20 (USP20), with an IC50 of 160 nM. Originally identified by GlaxoSmithKline (GSK) through compound screening, GSK2643943A blocks USP20-mediated deubiquitination, promoting the degradation of USP20 substrates such as HMGCR, ULK1, and CTSL. In preclinical studies, GSK2643943A has demonstrated anti-tumor efficacy, particularly in oral squamous cell carcinoma (OSCC), pancreatic ductal adenocarcinoma (PDAC), and T-cell acute lymphoblastic leukemia (T-ALL), often by enhancing the effects of oncolytic viruses (like oHSV-1) or other targeted therapies. It has also been investigated for its potential to attenuate macrophage foam cell formation and atherosclerosis.