Paralog Specificity Determines Subcellular Distribution, Action Mechanism, and Anticancer Activity of TRAP1 Inhibitors

Although Hsp90 inhibitors can inhibit
multiple tumorigenic pathways
in cancer cells, their anticancer activity has been disappointingly
modest. However, by forcing Hsp90 inhibitors into the mitochondria
with mitochondrial delivery vehicles, they were converted into potent
drugs targeting the mitochondrial Hsp90 paralog TRAP1. Here, to improve
mitochondrial drug accumulation without using the mitochondrial delivery
vehicle, we increased freely available drug concentrations in the
cytoplasm by reducing the binding of the drugs to the abundant cytoplasmic
Hsp90. After analyzing X-ray cocrystal structures, the purine ring
of the Hsp90 inhibitor 2 (BIIB021) was modified to pyrazolopyrimidine
scaffolds. One pyrazolopyrimidine, 12b (DN401), bound
better to TRAP1 than to Hsp90, inactivated the mitochondrial TRAP1
in vivo, and it exhibited potent anticancer activity. Therefore, the
rationale and feasible guidelines for developing 12b can
potentially be exploited to design a potent TRAP1 inhibitor.