7KIA

Crystal structure of FGFR2 kinase domain gatekeeper mutant V564F in complex with covalent compound 19

7KIA の概要

• エントリーDOI: 10.2210/pdb7kia/pdb
• 分子名称: 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)
• 機能のキーワード: fgfr kinase domain, fgfr, fgfr2, fgfr3, kinase inhibitor, covalent inhibitor, gatekeeper mutant, rtk, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 72052.72

構造登録者

Ke, J.,Wibowo, A.S.,Carter, J.J.,Larsen, N.A. (登録日: 2020-10-23, 公開日: 2021-02-10, 最終更新日: 2024-11-13)

主引用文献

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

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: 33488969
DOI: 10.1021/acsmedchemlett.0c00517

実験手法

X-RAY DIFFRACTION (2.22 Å)