ChemBioChem 2014-11-03

Reversible covalent inhibition of eEF-2K by carbonitriles.

Ashwini K Devkota, Ramakrishna Edupuganti, Chunli Yan, Yue Shi, Jiney Jose, Qiantao Wang, Tamer S Kaoud, Eun Jeong Cho, Pengyu Ren, Kevin N Dalby

Index: ChemBioChem. 15(16) , 2435-42, (2014)

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Abstract

eEF-2K is a potential target for treating cancer. However, potent specific inhibitors for this enzyme are lacking. Previously, we identified 2,6-diamino-4-(2-fluorophenyl)-4H-thiopyran-3,5-dicarbonitrile (DFTD) as an inhibitor of eEF-2K. Here we describe its mechanism of action against eEF-2K, on the basis of kinetic, mutational, and docking studies, and use chemoinformatic approaches to identify a similar class of carbonitrile-containing compounds that exhibit the same mechanism of action. We show that DFTD behaves as a reversible covalent inhibitor of eEF-2K with a two-step mechanism of inhibition: a fast initial binding step, followed by a slower reversible inactivation step. Molecular docking suggests that a nitrile group of DFTD binds within 4.5 Å of the active site Cys146 to form a reversible thioimidate adduct. Because Cys146 is not conserved amongst other related kinases, targeting this residue holds promise for the development of selective covalent inhibitors of eEF-2K. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.