Structure-Based Discovery of Hsp90/HDAC6 Dual Inhibitors Targeting Aggressive Prostate Cancer

HDAC6 and Heat Shock Protein 90 (Hsp90) are key regulators
within
the androgen response pathway, exhibiting a close interplay and mutual
interaction patterns that make their combined inhibition a promising
strategy for treating aggressive prostate cancer (PC). Herein, we
present the structure-based design of dual inhibitors of Hsp90 and
HDAC6 that leveraged the crystal structure requirements of HDAC6 and
two distinct Hsp90 binding pockets. The study led to the discovery
of compound 17, a potent, nearly balanced, and selective
dual inhibitor of HDAC6 and Hsp90 endowed with favorable drug-like
properties. The compound demonstrated excellent antiproliferative
activity across PC cell lines. In 3D tumor spheroid models, it demonstrated
marked anticancer activity and ability to target both established
tumor masses and tumor-initiating cell populations. Furthermore, combination
studies showed marked synergistic effects that outperformed the coadministration
of single-target inhibitors. Overall, compound 17 stands
as a promising candidate for further preclinical evaluation against
aggressive forms of PC.