/Lysosomal proteolysis facilitates the turnover of organelles and selected long-lived proteins and is a criticalregulator of cellular homeostasis. Its aberrant activation promotes drug resistance and cancer progression bygenerating alternative sources of survival sustaining metabolic fuel to cells that are stressed by hypoxia,radiation, chemotherapy, and targeted agents. Despite its clear potential as a therapeutic target, no intentionallydesigned targeted inhibitors of lysosomal function have been FDA approved to date. We recently generated aseries of novel orally available lysosomal disrupting agents with favorable safety profiles and single agenttherapeutic activity. Our first lead hit is active against acute myeloid leukemia (AML) cells with high-risk featuresand augments the efficacy of azacitidine to significantly extend overall survival in mouse models of AML. Ourmajor goal is to use medicinal chemistry approaches to optimize its pharmacologic properties to develop a novellysosomal proteolysis inhibitor that can be commercialized for the treatment of patients with AML and otherdiseases where aberrant pathway activity contributes to pathogenesis.
Public Health Relevance Statement: PROJECT NARRATIVE
Patients with acute myeloid leukemia (AML) have a dismal prognosis and new therapeutic approaches are
desperately needed. Our preliminary studies have identified the lysosomal proteolysis pathway as a selective
target for AML therapy. Here, we propose to optimize the pharmacological properties of our lead hit orally active
lysosomal disrupting agent to identify a lead compound that is a candidate for commercialization.
Project Terms: <5 AZC><5-AC><5-Aza-cytidine><5-Azacytidine>|
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