A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy
Abstract
Reprogramming mitochondrial functions supports tumor growth and may open up new therapeutic avenues. In this study, we focused on the mitochondrial protein folding environment by attaching a purine-based inhibitor of the molecular chaperone Heat Shock Protein-90 (Hsp90), known as PU-H71, to a mitochondrial-targeting molecule, triphenylphosphonium (TPP). The binding of PU-H71-TPP to ADP-Hsp90, the Hsp90 co-chaperone complex, or the mitochondrial Hsp90 homolog TRAP1 involved a series of interactions, including hydrogen bonds, π-π stacking, cation-π contacts, and hydrophobic interactions with the active site’s surrounding amino acids.
PU-H71-TPP showed a selective accumulation in the mitochondria of tumor cells, achieving a 17-fold increase in the mitochondrial-to-cytosol ratio, while unmodified PU-H71 had minimal mitochondrial localization. Treatment with PU-H71-TPP disrupted the mitochondrial membrane potential, inhibited oxidative phosphorylation in sensitive cell types, and decreased ATP production, ultimately leading to apoptosis and cell death in tumors. In contrast, unmodified PU-H71 had no effect.
Bioinformatics analysis revealed a “mitochondrial Hsp90” signature in Acute Myeloid Leukemia (AML), which is associated with poorer outcomes. Inhibition of mitochondrial Hsp90s was effective in killing primary and cultured AML cells, with little impact on normal peripheral blood mononuclear cells. These findings suggest that targeting Hsp90 inhibitors to mitochondria is a viable strategy that enhances anticancer efficacy. The potential “addiction” of AML HSP990 cells to mitochondrial Hsp90s may offer a promising new therapeutic target.