On November 8, 2021 The Genoscience Pharma’s team and its collaborators reported that they are happy of this new publication in Autophagy Journal showing that GNS561, a clinical-stage candidate, inhibiting PPT1, is efficient in Hepatocarcinoma via modulation of lysosomal functions (Press release, GenoScience, NOV 8, 2021, View Source [SID1234594825]).
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GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions Sonia Brun a,#, Eloïne Bestion a,b,#, Eric Raymond a,c,#, Firas Bassissia, Zuzana Macek Jilkova d,e,f, Soraya Mezouar a, Madani Rachida, Marie Novello a, Jennifer Tracza, Ahmed Hamaïg,h, Gilles Lalmanach i,j, Lise Vanderlyndeni,j, Raphael Legouffek, Jonathan Stauberl, Thomas Schubertm, Maximilian G. Plachm, Jérôme Courcambecka, Cyrille Drouota, Guillaume Jacquemota, Cindy Serdjebia, Gael Roth d,e,f, Jean-Pierre Baudoin b, Christelle Ansaldia, Thomas Decaens d,e,f,#, and Philippe Halfona,#
ABSTRACT
Hepatocellular carcinoma is the most frequent primary liver cancer. Macroautophagy/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 hepatocellular carcinoma in vivo models. We showed that due to its lysosomotropic properties, GNS561 could reach and specifically inhibited its enzyme target, PPT1 (palmitoyl-protein thioesterase 1), resulting in lysosomal unbound Zn2+ accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered location of MTOR (mechanistic target of rapamycin kinase), lysosomal membrane permeabilization, caspase activation and cell death. Accordingly, GNS561, for which a global phase 1b clinical trial in liver cancers was just successfully achieved, represents a promising new drug candidate and a hopeful therapeutic strategy in cancer treatment