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Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors

Lookup NU author(s): Professor Mike Waring



This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Chemical Society, 2020.

For re-use rights please refer to the publisher's terms and conditions.


With 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.

Publication metadata

Author(s): McAulay K, Hoyt EA, Thomas M, Schimpl M, Bodnarchuk MS, Lewis HJ, Barratt D, Bhavsar D, Robinson DM, Deery MJ, Ogg DJ, Bernardes GJL, Ward RA, Waring MJ, Kettle JG

Publication type: Article

Publication status: Published

Journal: Journal of the American Chemical Society

Year: 2020

Volume: 142

Issue: 23

Pages: 10358–10372

Print publication date: 10/06/2020

Online publication date: 15/05/2020

Acceptance date: 15/05/2020

Date deposited: 18/05/2020

ISSN (print): 0002-7863

ISSN (electronic): 1520-5126

Publisher: American Chemical Society


DOI: 10.1021/jacs.9b13391


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Funder referenceFunder name
AstraZeneca postdoctoral scheme
Herchel Smith Fellowship studentship
Royal Society University Research Fellowship