6XVB

Crystal structure of the kinase domain of human c-KIT with a cyclic imidate inhibitor covalently bound to Cys788

Summary for 6XVB

• Entry DOI: 10.2210/pdb6xvb/pdb
• Descriptor: Mast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit, ~{N}-(4,4-dimethyl-2-propyl-3,1-benzoxazin-6-yl)-2-[3-methoxy-5-(7-methoxyquinolin-4-yl)oxy-pyridin-2-yl]ethanamide (3 entities in total)
• Functional Keywords: type ii kinase inhibitor, structure-based drug design, covalent inhibitor, cysteine reactive warhead, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 75746.38

Authors

Schimpl, M.,McAuley, K.,Hoyt, E.A.,Thomas, M.,Bodnarchuk, M.S.,Lewis, H.J.,Barratt, D.,Deery, M.J.,Ogg, D.J.,Bernardes, G.J.L.,Ward, R.A.,Kettle, J.G.,Waring, M.J. (deposition date: 2020-01-21, release date: 2020-05-27, Last modification date: 2024-10-23)

Primary citation

McAulay, K.,Hoyt, E.A.,Thomas, M.,Schimpl, M.,Bodnarchuk, M.S.,Lewis, H.J.,Barratt, D.,Bhavsar, D.,Robinson, D.M.,Deery, M.J.,Ogg, D.J.,Bernardes, G.J.L.,Ward, R.A.,Waring, M.J.,Kettle, J.G.
Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.
J.Am.Chem.Soc., 142:10358-10372, 2020

PubMed Abstract: With a resurgence in interest in covalent drugs, there is a 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 pharmacokinetic profile relative to the related acrylamide-based inhibitor. In addition, the use of a novel heterocycle as a 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 while avoiding some of the limitations generally associated with established moieties.

PubMed: 32412754
DOI: 10.1021/jacs.9b13391

Experimental method

X-RAY DIFFRACTION (2.15 Å)