6DQ8

LINKED KDM5A JMJ DOMAIN BOUND TO THE INHIBITOR N49 i.e. 2-((2-chlorophenyl)(2-(1-methylpyrrolidin-2-yl)ethoxy)methyl)thieno[3,2-b]pyridine-7-carboxylic acid

Summary for 6DQ8

• Entry DOI: 10.2210/pdb6dq8/pdb
• Descriptor: Linked KDM5A Jmj Domain, 2-[(R)-(2-chlorophenyl){2-[(2S)-1-methylpyrrolidin-2-yl]ethoxy}methyl]thieno[3,2-b]pyridine-7-carboxylic acid, 2-[(S)-(2-chlorophenyl){2-[(2S)-1-methylpyrrolidin-2-yl]ethoxy}methyl]thieno[3,2-b]pyridine-7-carboxylic acid, ... (8 entities in total)
• Functional Keywords: demethylase inhibition, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 39176.07

Authors

Horton, J.R.,Cheng, X. (deposition date: 2018-06-10, release date: 2018-11-21, Last modification date: 2023-10-11)

Primary citation

Horton, J.R.,Woodcock, C.B.,Chen, Q.,Liu, X.,Zhang, X.,Shanks, J.,Rai, G.,Mott, B.T.,Jansen, D.J.,Kales, S.C.,Henderson, M.J.,Cyr, M.,Pohida, K.,Hu, X.,Shah, P.,Xu, X.,Jadhav, A.,Maloney, D.J.,Hall, M.D.,Simeonov, A.,Fu, H.,Vertino, P.M.,Cheng, X.
Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A.
J. Med. Chem., 61:10588-10601, 2018

PubMed 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.

PubMed: 30392349
DOI: 10.1021/acs.jmedchem.8b01219

Experimental method

X-RAY DIFFRACTION (1.46 Å)