6V79

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 (CD2) complexed with NF2376

Summary for 6V79

• Entry DOI: 10.2210/pdb6v79/pdb
• Descriptor: Hdac6 protein, ZINC ION, POTASSIUM ION, ... (6 entities in total)
• Functional Keywords: histone deacetylase, hydrolase
• Biological source: Danio rerio (Zebrafish)
• Total number of polymer chains: 2
• Total formula weight: 81667.14

Authors

Osko, J.D.,Christianson, D.W. (deposition date: 2019-12-08, release date: 2020-12-02, Last modification date: 2023-10-11)

Primary citation

Campiani, G.,Cavella, C.,Osko, J.D.,Brindisi, M.,Relitti, N.,Brogi, S.,Saraswati, A.P.,Federico, S.,Chemi, G.,Maramai, S.,Carullo, G.,Jaeger, B.,Carleo, A.,Benedetti, R.,Sarno, F.,Lamponi, S.,Rottoli, P.,Bargagli, E.,Bertucci, C.,Tedesco, D.,Herp, D.,Senger, J.,Ruberti, G.,Saccoccia, F.,Saponara, S.,Gorelli, B.,Valoti, M.,Kennedy, B.,Sundaramurthi, H.,Butini, S.,Jung, M.,Roach, K.M.,Altucci, L.,Bradding, P.,Christianson, D.W.,Gemma, S.,Prasse, A.
Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors.
J.Med.Chem., 64:9960-9988, 2021

PubMed 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 HDAC6 inhibitors, having low inhibitory potency over HDAC1 and HDAC8, as potential pharmacological tools for IPF treatment. Their inhibitory potency was combined with low and toxicity. Structural analysis of 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 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.

PubMed: 34251197
DOI: 10.1021/acs.jmedchem.1c00184

Experimental method

X-RAY DIFFRACTION (2.03951514036 Å)