Ezurpimtrostat hydrochloride (GNS561) is a novel lysosomotropic agent and autophagy inhibitor that induces lysosomal cell death, targets palmitoyl-protein thioesterase 1 (PPT1). GNS561 induced a dramatic increase of CSC death in both HCC and liver mCRC cell lines, displays antitumor properties in HCC in vivo models. GNS561 activates the caspase-dependent apoptosis pathway, induces lysosomal membrane permeabilization and cathepsin-dependent cell death in HepG2 cells. GNS561 showed potent antitumor activity ranging from 0.22 uM for the most sensitive cell line (LN-18, a glioblastoma cell line) to 7.27 uM for the least sensitive cell line (OVCAR3, ovarian cancer cell line). GNS561 was at least 10-fold more effective than HCQ in tested cancer cell lines, also displayed activity in primary HCC patient-derived cells and was on average 3-fold more potent than sorafenib. GNS561 exhibits potent antiviral activity against SARS-CoV-2 through autophagy inhibition.
