Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A
| Autor: | Matthew D. Hall, Stephen C. Kales, John R. Shanks, Clayton B. Woodcock, Katherine Pohida, Ganesha Rai, Xin Xu, Xiaodong Cheng, Qin Chen, Bryan T. Mott, Xing Zhang, Daniel J. Jansen, David J. Maloney, Ajit Jadhav, Matthew G. Cyr, Xin Hu, Pranav Shah, John R. Horton, Xu Liu, Haian Fu, Paula M. Vertino, Mark J. Henderson, Anton Simeonov |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Histone H3 Lysine 4 Stereochemistry Protein Conformation Lysine Article Cell Line 03 medical and health sciences 0302 clinical medicine Drug Discovery Moiety Humans Enzyme Inhibitors Acrylamide biology Chemistry Oxidoreductase inhibitor 030104 developmental biology Histone 030220 oncology & carcinogenesis KDM5A Drug Design biology.protein Molecular Medicine Demethylase Retinoblastoma-Binding Protein 2 Cysteine |
| Popis: | The active sites of hundreds of human α-ketoglutarate (αKG) and Fe(II)-dependent dioxygenases are exceedingly well preserved, which challenges the design of selective inhibitors. We identified a noncatalytic cysteine (Cys481 in KDM5A) near the active sites of KDM5 histone H3 lysine 4 demethylases, which is absent in other histone demethylase families, that could be explored for interaction with the cysteine-reactive electrophile acrylamide. We synthesized analogs of a thienopyridine-based inhibitor chemotype, namely, 2-((3-aminophenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2- b]pyridine-7-carboxylic acid (N70) and a derivative containing a (dimethylamino)but-2-enamido)phenyl moiety (N71) designed to form a covalent interaction with Cys481. We characterized the inhibitory and binding activities against KDM5A and determined the cocrystal structures of the catalytic domain of KDM5A in complex with N70 and N71. Whereas the noncovalent inhibitor N70 displayed αKG-competitive inhibition that could be reversed after dialysis, inhibition by N71 was dependent on enzyme concentration and persisted even after dialysis, consistent with covalent modification. |
| Databáze: | OpenAIRE |
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