| References: |
ROC-325 is a novel orally available autophagy inhibitor that is well tolerated, significantly more potent than HCQ, and has promising anti-AML activity. ROC-325 as a novel agent for the treatment of AML and other disorders where lysosomal activity contributes to disease pathogenesis.In vitro treatment of a panel of human AML cell lines and normal human bone marrow progenitors demonstrated that ROC-325 diminished AML cell viability (IC50 range 0.7-2.2 µM), antagonized clonogenic survival, and induced apoptosis in a manner that was therapeutically selective. Analysis of primary blasts from patients with AML showed that its activity was not significantly affected by adverse cytogenetics or multi-drug resistance due to relapsed/refractory clinical status. Oral administration of 50 mg/kg ROC-325 (QDx5) to mice bearing disseminated MV4-11 human AML xenografts significantly increased lifespan (P<0.05) and enhanced the efficacy of azacitidine (5 mg/kg IV, 2X per week). ROC-325 was well tolerated and no notable toxicities were observed other than a modest, non-significant reversible reduction in mean body weight. Immunohistochemical analysis of specimens collected from animals treated with ROC-325 demonstrated significant increases in the autophagic markers LC3B and p62 and apoptotic blasts. |
