Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors.

Abstract

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive-fibrosing phenotype. IPF has been associated with aberrant HDAC activities confirmed by our immunohistochemistry studies on HDAC6 overexpression in IPF lung tissues. We herein developed a series of novel hHDAC6 inhibitors, having low inhibitory potency over hHDAC1 and hHDAC8, as potential pharmacological tools for IPF treatment. Their inhibitory potency was combined with low in vitro and in vivo toxicity. Structural analysis of 6h and structure-activity relationship studies contributed to the optimization of the binding mode of the new molecules. The best-performing analogues were tested for their efficacy in inhibiting fibrotic sphere formation and cell viability, proving their capability in reverting the IPF phenotype. The efficacy of analogue 6h was also determined in a validated human lung model of TGF-β1-dependent fibrogenesis. The results highlighted in this manuscript may pave the way for the identification of first-in-class molecules for the treatment of IPF.

• Authors: Giuseppe Campiani, Caterina Cavella, Jeremy D Osko, Margherita Brindisi, Nicola Relitti, Simone Brogi, A Prasanth Saraswati, Stefano Federico, Giulia Chemi, Samuele Maramai, Gabriele Carullo, Benedikt Jaeger, Alfonso Carleo, Rosaria Benedetti, Federica Sarno, Stefania Lamponi, Paola Rottoli, Elena Bargagli, Carlo Bertucci, Daniele Tedesco, Daniel Herp, Johanna Senger, Giovina Ruberti, Fulvio Saccoccia, Simona Saponara, Beatrice Gorelli, Massimo Valoti, Breándan Kennedy, Husvinee Sundaramurthi, Stefania Butini, Manfred Jung, Katy M Roach, Lucia Altucci, Peter Bradding, David W Christianson, Sandra Gemma, Antje Prasse
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 14 Pg. 9960-9988 (07 22 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34251197 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Histone Deacetylase Inhibitors
• HDAC6 protein, human
• Histone Deacetylase 6

Topics

• Dose-Response Relationship, Drug
• Drug Design
• Histone Deacetylase 6 (antagonists & inhibitors, metabolism)
• Histone Deacetylase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Idiopathic Pulmonary Fibrosis (drug therapy, metabolism, pathology)
• Models, Molecular
• Molecular Structure
• Structure-Activity Relationship