A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy.

A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy. Oncotarget. 2017 Dec 22;8(68):112184-112198 Authors: Bryant KG, Chae YC, Martinez RL, Gordon JC, Elokely KM, Kossenkov AV, Grant S, Childers WE, Abou-Gharbia M, Altieri DC Abstract 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, π-π stacking, cation-π 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 m...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research