Novel Benzohydroxamate-Based Potent and Selective Histone Deacetylase 6 (HDAC6) Inhibitors Bearing a Pentaheterocyclic Scaffold: Design, Synthesis, and Biological Evaluation PMID: 31710483

ADC Targets in Oncology

2026-04-10

Novel Benzohydroxamate-Based Potent and Selective Histone Deacetylase 6 (HDAC6) Inhibitors Bearing a Pentaheterocyclic Scaffold: Design, Synthesis, and Biological Evaluation

J Med Chem. 2019 Dec 12;62(23):10711-10739. doi: 10.1021/acs.jmedchem.9b01194.

Barbara Vergani ¹ , Giovanni Sandrone ¹ , Mattia Marchini ¹ , Chiara Ripamonti ¹ , Edoardo Cellupica ¹ , Elisabetta Galbiati ¹ , Gianluca Caprini ¹ , Gianfranco Pavich ¹ , Giulia Porro ¹ , Ilaria Rocchio ¹ , Maria Lattanzio ¹ , Marcello Pezzuto ¹ , Malgorzata Skorupska ¹ , Paola Cordella ¹ , Paolo Pagani ¹ , Pietro Pozzi ¹ , Roberta Pomarico ¹ , Daniela Modena ¹ , Flavio Leoni ¹ , Raffaella Perego ¹ , Gianluca Fossati ¹ , Christian Steinkühler ¹ , Andrea Stevenazzi ¹

Affiliations

Abstract

Histone deacetylase 6 (HDAC6) is a peculiar HDAC isoform whose expression and functional alterations have been correlated with a variety of pathologies such as autoimmune disorders, neurodegenerative diseases, and Cancer. It is primarily a cytoplasmic protein, and its deacetylase activity is focused mainly on nonhistone substrates such as tubulin, heat shock protein (HSP)90, Foxp3, and cortactin, to name a few. Selective inhibition of HDAC6 does not show cytotoxic effects in healthy cells, normally associated with the inhibition of Class I HDAC isoforms. Here, we describe the design and synthesis of a new class of potent and selective HDAC6 inhibitors that bear a pentaheterocyclic central core. These compounds show a remarkably low toxicity both in vitro and in vivo and are able to increase the function of regulatory T cells (Tregs) at well-tolerated concentrations, suggesting a potential clinical use for the treatment of degenerative, autoimmune diseases and for organ transplantation.