2. Academic Validation
  3. Structure-Based Discovery of Hsp90/HDAC6 Dual Inhibitors Targeting Aggressive Prostate Cancer

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

  • J Med Chem. 2025 Aug 14;68(15):15738-15765. doi: 10.1021/acs.jmedchem.5c00717.
Andrea Citarella 1 2,  Silvia Belluti 1,  Davide Bonanni 1,  Davide Moi 1 2,  Isabella Piccinini 1,  Arianna Rinaldi 1,  Chiara Papulino 3,  Rosaria Benedetti 3 4,  Laura Cuoghi 1,  Stefano Di Ciolo 2,  Alessandra Silvani 2,  Lucia Altucci 3 4 5,  Luca Pinzi 1,  Silvia Franchini 1,  Daniele Passarella 2,  Claudia Sorbi 1,  Clelia Giannini 2,  Carol Imbriano 1,  Giulio Rastelli 1
Affiliations

Affiliations

  • 1 Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena 41125, Italy.
  • 2 Department of Chemistry, University of Milan, Via Golgi 19, Milano 20133, Italy.
  • 3 Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
  • 4 Program of Medical Epigenetics, Vanvitelli Hospital, Naples 80138, Italy.
  • 5 Biogem Institute of Molecular and Genetic Biology, Ariano 83031, Irpino, Italy.
PMID: 40699153 DOI: 10.1021/acs.jmedchem.5c00717
Abstract

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.

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