7JYS

hALK in complex with 3-(3-chlorophenyl)-5-methyl-1H-pyrazole

7JYS の概要

• エントリーDOI: 10.2210/pdb7jys/pdb
• 関連するPDBエントリー: 7JYR
• 分子名称: ALK tyrosine kinase receptor, 3-(3-chlorophenyl)-5-methyl-1H-pyrazole, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: alk tyrosine kinase receptor, inhibitor, complex, kinase, sbdd, transferase-inhibitor complex, 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: 36300.08

構造登録者

McGrath, A.P.,Zou, H.,Lane, W.,Saikatendu, K. (登録日: 2020-08-31, 公開日: 2021-01-20, 最終更新日: 2023-10-18)

主引用文献

Fujimori, I.,Wakabayashi, T.,Murakami, M.,Okabe, A.,Ishii, T.,McGrath, A.,Zou, H.,Saikatendu, K.S.,Imoto, H.
Discovery of Novel and Highly Selective Cyclopropane ALK Inhibitors through a Fragment-Assisted, Structure-Based Drug Design.
Acs Omega, 5:31984-32001, 2020

PubMed Abstract: Fragment screening is frequently used for hit identification. However, there was no report starting from a small fragment for the development of an anaplastic lymphoma kinase (ALK) inhibitor, despite the number of ALK inhibitors reported. We began our research with the fragment hit and our subsequent linker design, and its docking analysis yielded novel -1,2,2-trisubstituted cyclopropane . The fragment information was integrated with a structure-based approach to improve upon the selectivity over tropomyosin receptor kinase A, leading to the potent and highly selective ALK inhibitor, 4-trifluoromethylphenoxy--1,2,2-trisubstituted cyclopropane . This work shows that fragments become a powerful tool for both lead generation and optimization, such as the improvement of selectivity, by combining them with a structure-based drug design approach, resulting in the fast and efficient development of a novel, potent, and highly selective compound.

PubMed: 33344853
DOI: 10.1021/acsomega.0c04900

実験手法

X-RAY DIFFRACTION (2.22 Å)