GNS561, a clinical-stage PPT1 inhibitor, has powerful antitumor activity against hepatocellular carcinoma via modulation of lysosomal functions

SUMMARY

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer. Autophagy inhibitors have been extensively studied in cancer but, to date, none has reached efficacy in clinical trials. In this study, we demonstrated that GNS561, a new autophagy inhibitor, whose anticancer activity was previously linked to lysosomal cell death, displayed high liver tropism and potent antitumor activity against a panel of human cancer cell lines and in two HCC in vivo models. We showed that GNS561, which is an effective lysosomotropic agent, can reach and inhibit its enzyme target, palmitoyl-protein thioesterase 1, resulting in lysosomal unbound Zn²⁺ accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered location of mTOR, lysosomal membrane permeabilization, caspase activation and cell death. Accordingly, GNS561, currently tested in a global Phase 1b/2a clinical trial against primary liver cancer, represents a promising new drug candidate and a hopeful therapeutic strategy in cancer treatment.