Alkynyl benzoxazines and dihydroquinazolines as cysteine targeting covalent warheads and their application in identification of selective irreversible kinase inhibitors

DOI: 10.1021/jacs.9b13391

Authors: Kirsten Mcaulay (AstraZeneca) , Emily A. Hoyt (University of Cambridge) , Morgan Thomas (AstraZeneca) , Marianne Schimpl (AstraZeneca) , Michael S. Bodnarchuk (AstraZeneca) , Hilary J. Lewis (AstraZeneca) , Derek Barratt (AstraZeneca) , Deepa Bhavsar (AstraZeneca) , David M. Robinson (University of Cambridge) , Michael J. Deery (University of Cambridge) , Derek Ogg (AstraZeneca) , Gonçalo J. I. Bernardes (University of Cambridge; Univerisdad de Lisboa) , Richard A. Ward (Newcastle University) , Michael J. Waring (Newcastle University) , Jason G. Kettle (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of The American Chemical Society

State: Published (Approved)
Published: May 2020
Diamond Proposal Number(s): 12419 , 20015

Abstract: 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.

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 27/05/2020 09:57

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)