| Literature DB >> 30392349 |
John R Horton1,2, Clayton B Woodcock1, Qin Chen1, Xu Liu2, Xing Zhang1, John Shanks2, Ganesha Rai3, Bryan T Mott3, Daniel J Jansen3, Stephen C Kales3, Mark J Henderson3, Matthew Cyr3, Katherine Pohida3, Xin Hu3, Pranav Shah3, Xin Xu3, Ajit Jadhav3, David J Maloney3, Matthew D Hall3, Anton Simeonov3, Haian Fu, Paula M Vertino, Xiaodong Cheng1,2.
Abstract
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.Entities:
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Year: 2018 PMID： 30392349 PMCID： PMC6467790 DOI： 10.1021/acs.jmedchem.8b01219
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446