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Bryant KG , Chae YC , Martinez RL , Gordon JC , Elokely KM , Kossenkov AV , Grant S , Childers WE , Abou-Gharbia M , Altieri DC
A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy
Oncotarget. 2017 Dec 22;8(68) :112184-112198
PMID: 29348817    PMCID: PMC5762502   
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Reprogramming of mitochondrial functions sustains tumor growth and may provide therapeutic opportunities. Here, we targeted the protein folding environment in mitochondria by coupling a purine-based inhibitor of the molecular chaperone Heat Shock Protein-90 (Hsp90), PU-H71 to the mitochondrial-targeting moiety, triphenylphosphonium (TPP). Binding of PU-H71-TPP to ADP-Hsp90, Hsp90 co-chaperone complex or mitochondrial Hsp90 homolog, TRAP1 involved hydrogen bonds, pi-pi stacking, cation-pi contacts and hydrophobic interactions with the surrounding amino acids in the active site. PU-H71-TPP selectively accumulated in mitochondria of tumor cells (17-fold increase in mitochondria/cytosol ratio), whereas unmodified PU-H71 showed minimal mitochondrial localization. Treatment of tumor cells with PU-H71-TPP dissipated mitochondrial membrane potential, inhibited oxidative phosphorylation in sensitive cell types, and reduced ATP production, resulting in apoptosis and tumor cell killing. Unmodified PU-H71 had no effect. Bioinformatics analysis identified a "mitochondrial Hsp90" signature in Acute Myeloid Leukemia (AML), which correlates with worse disease outcome. Accordingly, inhibition of mitochondrial Hsp90s killed primary and cultured AML cells, with minimal effects on normal peripheral blood mononuclear cells. These data demonstrate that directing Hsp90 inhibitors with different chemical scaffolds to mitochondria is feasible and confers improved anticancer activity. A potential "addiction" to mitochondrial Hsp90s may provide a new therapeutic target in AML.
1949-2553 Bryant, Kelly G Chae, Young Chan Martinez, Rogelio L Gordon, John C Elokely, Khaled M Kossenkov, Andrew V Grant, Steven Childers, Wayne E Abou-Gharbia, Magid Altieri, Dario C R01 CA078810/CA/NCI NIH HHS/United States R01 CA205607/CA/NCI NIH HHS/United States UH2 TR001373/TR/NCATS NIH HHS/United States P01 CA140043/CA/NCI NIH HHS/United States P30 CA010815/CA/NCI NIH HHS/United States R01 CA167708/CA/NCI NIH HHS/United States R01 CA190027/CA/NCI NIH HHS/United States Journal Article United States Oncotarget. 2017 Dec 11;8(68):112184-112198. doi: 10.18632/oncotarget.23097. eCollection 2017 Dec 22.