7kie

Crystal structure of FGFR2 kinase domain gatekeeper mutant V564F in complex with covalent compound 3

spinqualitylabelsall models 7kie, resolution 2.47Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.47Å Ligands: FLC, GOL, WF7 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3.,Brawn RA, Cook A, Omoto K, Ke J, Karr C, Colombo F, Virrankoski M, Prajapati S, Reynolds D, Bolduc DM, Nguyen TV, Gee P, Borrelli D, Caleb B, Yao S, Irwin S, Larsen NA, Selvaraj A, Zhao X, Ioannidis S ACS Med Chem Lett. 2020 Dec 2;12(1):93-98. doi: 10.1021/acsmedchemlett.0c00517., eCollection 2021 Jan 14. PMID:33488969 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Fibroblast growth factor receptor 3D receptor

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