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.