9U7E

FGFR2 kinase domain with a macrocyclic compound 8g

これはPDB形式変換不可エントリーです。

9U7E の概要

• エントリーDOI: 10.2210/pdb9u7e/pdb
• 分子名称: Fibroblast growth factor receptor 2, (E)-4-methyl-17-(1-methyl-1H-pyrazol-4-yl)-7,10-dioxa-4-aza-1(3,6)-imidazo[1,2-b]pyridazina-2(3,5)-pyridinacyclodecaphan-3-one, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: fibroblast growth factor receptor 2, 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: 70961.55

構造登録者

Chen, X.J.,Chen, Y.H. (登録日: 2025-03-24, 公開日: 2026-01-21)

主引用文献

Xiang, S.,Chen, X.,Lin, J.,Lin, X.,Lin, Q.,Song, X.,Yan, L.,Peng, H.,Tu, Z.,Patterson, A.V.,Smaill, J.B.,Tu, Y.,Chen, Y.,Lu, X.
Design, Synthesis, and Biological Evaluation of the First Novel Macrocycle-Based FGFR Inhibitors That Overcome Clinically Acquired Resistance.
J.Med.Chem., 2026

PubMed Abstract: Alterations in the FGFR family act as oncogenic drivers for multiple pediatric and adult tumors, leading to the development and approval of several FGFR inhibitors. However, the on-target gatekeeper and "molecular brake" mutations confer clinically acquired resistance to the FDA-approved FGFR inhibitors, which presents a significant unmet medical need. Herein, we report the first novel macrocycle-based FGFR inhibitors targeting both wild-type and clinically acquired variants of the FGFR family. The representative compound potently inhibited FGFR1/2/3 with IC values of 10.0, 6.9, and 30.2 nM, respectively. Compound also potently suppressed proliferation of a series of FGFR-driven cancer cell lines with IC values of 2.0-13.3 nM. Compared with futibatinib, exhibited superior inhibitory activity toward FGFR1, FGFR2, and FGFR2 mutations with IC values of 6.8, 0.7, and 0.8 nM, respectively. Moreover, demonstrated favorable antitumor efficacy in an RT112/84 bladder cancer xenograft model. This work provides a promising macrocycle-based lead compound for the treatment of FGFR-driven cancers.

PubMed: 41490805
DOI: 10.1021/acs.jmedchem.5c02462

実験手法

X-RAY DIFFRACTION (2.2 Å)