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

• DOI: 10.1021/jacs.9b13391
• Publication Date: 2020-05-16T00:47:32Z
• Authors: Kirsten McAulay; Emily A. Hoyt; Morgan Thomas; Marianne Schimpl; Michael S. Bodnar...; Hilary J. Lewis; Derek Barratt; Deepa Bhavsar; David M. Robinson; Michael J. Deery; Derek J. Ogg; Gonçalo J. L. Ber...; Richard A. Ward; Michael J. Waring; Jason G. Kettle
• Keywords: Kinome; Bioorthogonal Chemistry

With a resurgence in interest 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 alkynyl benzoxazine and dihydroquinazoline reaction with cysteine. Their utility alternative electrophilic warheads for chemical biological probes drug molecules demonstrated through site-selective protein modification incorporation into kinase scaffolds. A potent inhibitor JAK3 was identified superior selectivity across kinome improvements vitro pharmacokinetic profile relative related acrylamide-based inhibitor. In addition, use novel heterocycle reactive warhead target Cys788 c-KIT, where acrylamide has previously failed form interactions. These selective heterocyclic supplement current repertoire while avoiding some limitations generally associated established moieties.