8Y22

FGFR1 kinase domain with a covalent inhibitor 9g

これはPDB形式変換不可エントリーです。

8Y22 の概要

• エントリーDOI: 10.2210/pdb8y22/pdb
• 分子名称: Fibroblast growth factor receptor 1, ~{N}-[4-[[4-azanyl-3-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]phenyl]propanamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: fibroblast growth factor receptor 1, transferase
• 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: 71838.27

構造登録者

Chen, X.J.,Chen, Y.H. (登録日: 2024-01-25, 公開日: 2024-06-26, 最終更新日: 2024-10-30)

主引用文献

Deng, W.,Chen, X.,Liang, H.,Song, X.,Xiang, S.,Guo, J.,Tu, Z.,Zhou, Y.,Chen, Y.,Lu, X.
Design, synthesis and biological evaluation of 5-amino-1H-pyrazole-4-carboxamide derivatives as pan-FGFR covalent inhibitors.
Eur.J.Med.Chem., 275:116558-116558, 2024

PubMed Abstract: The aberrant activation of FGFRs plays a critical role in various cancers, leading to the development of several FGFR inhibitors in clinic. However, the emergence of drug resistance, primarily due to gatekeeper mutations in FGFRs, has limited their clinical efficacy. To address the unmet medical need, a series of 5-amino-1H-pyrazole-4-carboxamide derivatives were designed and synthesized as novel pan-FGFR covalent inhibitors targeting both wild-type and the gatekeeper mutants. The representative compound 10h demonstrated nanomolar activities against FGFR1, FGFR2, FGFR3 and FGFR2 V564F gatekeeper mutant in biochemical assays (IC = 46, 41, 99, and 62 nM). Moreover, 10h also strongly suppressed the proliferation of NCI-H520 lung cancer cells, SNU-16 and KATO III gastric cancer cells with IC values of 19, 59, and 73 nM, respectively. Further X-ray co-crystal structure revealed that 10h irreversibly binds to FGFR1. The study provides a new promising point for anticancer drug development medicated by FGFRs.

PubMed: 38870833
DOI: 10.1016/j.ejmech.2024.116558

実験手法

X-RAY DIFFRACTION (2.792 Å)