| Literature DB >> 34251197 |
Giuseppe Campiani1, Caterina Cavella1, Jeremy D Osko2, Margherita Brindisi1, Nicola Relitti1, Simone Brogi3, A Prasanth Saraswati1, Stefano Federico1, Giulia Chemi1, Samuele Maramai1, Gabriele Carullo1, Benedikt Jaeger4, Alfonso Carleo4, Rosaria Benedetti5, Federica Sarno5, Stefania Lamponi1, Paola Rottoli6, Elena Bargagli7, Carlo Bertucci8, Daniele Tedesco8, Daniel Herp9, Johanna Senger9, Giovina Ruberti10, Fulvio Saccoccia10, Simona Saponara11, Beatrice Gorelli11, Massimo Valoti11, Breándan Kennedy12, Husvinee Sundaramurthi12, Stefania Butini1, Manfred Jung9, Katy M Roach13, Lucia Altucci5, Peter Bradding13, David W Christianson2, Sandra Gemma1, Antje Prasse4.
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.Entities:
Mesh：
Substances：
Year: 2021 PMID： 34251197 PMCID： PMC8300879 DOI： 10.1021/acs.jmedchem.1c00184
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039