7DHL

Crystal structure of FGFR3 in complex with pyrimidine derivative

7DHL の概要

• エントリーDOI: 10.2210/pdb7dhl/pdb
• 分子名称: Fibroblast growth factor receptor 3, 5-[2-(3,5-dimethoxyphenyl)ethyl]-N-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidin-2-amine (3 entities in total)
• 機能のキーワード: protein kinase, signaling protein, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36211.44

構造登録者

Echizen, Y.,Tateishi, Y.,Amano, Y. (登録日: 2020-11-16, 公開日: 2021-02-03, 最終更新日: 2024-11-06)

主引用文献

Kuriwaki, I.,Kameda, M.,Iikubo, K.,Hisamichi, H.,Kawamoto, Y.,Kikuchi, S.,Moritomo, H.,Kondoh, Y.,Terasaka, T.,Amano, Y.,Tateishi, Y.,Echizen, Y.,Iwai, Y.,Noda, A.,Tomiyama, H.,Nakazawa, T.,Hirano, M.
Synthesis and structure-activity relationships of pyrimidine derivatives as potent and orally active FGFR3 inhibitors with both increased systemic exposure and enhanced in vitro potency.
Bioorg.Med.Chem., 33:116019-116019, 2021

PubMed Abstract: Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of patients with bladder cancer harboring genetic alterations in FGFR3. We identified pyrimidine derivative 20b, which induced tumor regression following oral administration to a bladder cancer xenograft mouse model. Compound 20b was discovered by optimizing lead compound 1, which we reported previously. Specifically, reducing the molecular size of the substituent at the 4-position and replacing the linker of the 5-position in the pyrimidine scaffold resulted in an increase in systemic exposure. Furthermore, introduction of two fluorine atoms into the 3,5-dimethoxyphenyl ring enhanced FGFR3 inhibitory activity. Molecular dynamics (MD) simulation of 20b suggested that the fluorine atom interacts with the main chain NH moiety of Asp635 via a hydrogen bond.

PubMed: 33486159
DOI: 10.1016/j.bmc.2021.116019

実験手法

X-RAY DIFFRACTION (2.57 Å)