7KIA
Crystal structure of FGFR2 kinase domain gatekeeper mutant V564F in complex with covalent compound 19
Summary for 7KIA
| Entry DOI | 10.2210/pdb7kia/pdb |
| Descriptor | Fibroblast growth factor receptor 2, 1-[4-(4-{4-(4-methylpiperazin-1-yl)-6-[(3-methyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}phenyl)piperidin-1-yl]prop-2-en-1-one, CITRATE ANION, ... (5 entities in total) |
| Functional Keywords | fgfr kinase domain, fgfr, fgfr2, fgfr3, kinase inhibitor, covalent inhibitor, gatekeeper mutant, rtk, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 72052.72 |
| Authors | Ke, J.,Wibowo, A.S.,Carter, J.J.,Larsen, N.A. (deposition date: 2020-10-23, release date: 2021-02-10, Last modification date: 2024-11-13) |
| Primary citation | Brawn, R.A.,Cook, A.,Omoto, K.,Ke, J.,Karr, C.,Colombo, F.,Virrankoski, M.,Prajapati, S.,Reynolds, D.,Bolduc, D.M.,Nguyen, T.V.,Gee, P.,Borrelli, D.,Caleb, B.,Yao, S.,Irwin, S.,Larsen, N.A.,Selvaraj, A.,Zhao, X.,Ioannidis, S. Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3. Acs Med.Chem.Lett., 12:93-98, 2021 Cited by PubMed Abstract: Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations. Using a combination of targeted high-throughput screening and structure-based drug design, we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR analysis and structure-based drug design led to analogues with improved potency and drug metabolism and pharmacokinetics properties. PubMed: 33488969DOI: 10.1021/acsmedchemlett.0c00517 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.22 Å) |
Structure validation
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