title: Drain the lysosome: Development of the novel orally available autophagy inhibitor ROC-325.
abstract: Although macroautophagy/autophagy is a key contributor to malignant pathogenesis and therapeutic resistance, there are few FDA-approved agents that significantly affect this pathway. We used medicinal chemistry strategies to develop ROC-325, an orally available novel inhibitor of lysosomal-mediated autophagy. Detailed in vitro and in vivo studies in preclinical models of renal cell carcinoma demonstrated that ROC-325 triggered the hallmark features of lysosomal autophagy inhibition, was very well tolerated, and exhibited significant superiority with respect to autophagy inhibition and anticancer activity over hydroxychloroquine. Our findings support the clinical investigation of the safety and preliminary efficacy of ROC-325 in patients with autophagy-dependent malignancies and other disorders where aberrant autophagy contributes to disease pathogenesis.
authors.affiliation: a Department of Medicine , Division of Translational and Regenerative Medicine, University of Arizona Cancer Center , Tucson , AZ , USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Carew
authors.affiliation: a Department of Medicine , Division of Translational and Regenerative Medicine, University of Arizona Cancer Center , Tucson , AZ , USA.
authors.forename: Steffan T
authors.initials: ST
authors.lastname: Nawrocki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D002986:Clinical Trials as Topic; D006801:Humans; D006886:Hydroxychloroquine / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice
chemical_list: D000970:Antineoplastic Agents; D006886:Hydroxychloroquine
keywords: ROC-325; autophagy inhibitor; hydroxychloroquine; lucanthone; renal cell carcinoma