6XVJ
Crystal structure of the KDR (VEGFR2) kinase domain in complex with a type-II inhibitor
Summary for 6XVJ
| Entry DOI | 10.2210/pdb6xvj/pdb |
| Descriptor | Vascular endothelial growth factor receptor 2, ~{N}-[3-[(dimethylamino)methyl]-5-methyl-phenyl]-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, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 37476.17 |
| 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: 2020-01-22, release date: 2020-05-27, Last modification date: 2024-05-01) |
| 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 Cited by 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: 32412754DOI: 10.1021/jacs.9b13391 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.78 Å) |
Structure validation
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