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Crystal structure of the kinase domain of human c-KIT with a cyclic imidate inhibitor covalently bound to Cys788Crystal structure of the kinase domain of human c-KIT with a cyclic imidate inhibitor covalently bound to Cys788
Structural highlights
Publication Abstract from PubMedWith a resurgence in interest in covalent drugs, there is need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery of new alkynyl benzoxazine and dihydroquinazoline moieties capable of covalent reaction with cysteine. Their utility as alternative electrophilic warheads for chemical biological probes and drug molecules is demonstrated through site-selective protein modification and incorporation into kinase drug scaffolds. A potent covalent inhibitor of JAK3 kinase was identified with superior selectivity across the kinome and improvements in in vitro pharmacokinetic profile relative to the related acrylamide-based inhibitor. In addition, the use of a novel heterocycle as cysteine reactive warhead is employed to target Cys788 in c-KIT where acrylamide has previously failed to form covalent interactions. These new reactive and selective heterocyclic warheads supplement the current repertoire for cysteine covalent modification whilst avoiding some of the limitations generally associated with established moieties. Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.,McAulay K, Hoyt EA, Thomas M, Schimpl M, Bodnarchuk MS, Lewis HJ, Barratt D, Bhavsar D, Robinson DM, Deery MJ, Ogg D, Bernardes GJL, Ward RA, Waring MJ, Kettle JG J Am Chem Soc. 2020 May 15. doi: 10.1021/jacs.9b13391. PMID:32412754[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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