6ACR

Crystal structure of human ALK2 kinase domain with R206H mutation in complex with RK-59638

6ACR の概要

• エントリーDOI: 10.2210/pdb6acr/pdb
• 分子名称: Activin receptor type-1, N-(4-methoxyphenyl)-4-[3-(pyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, kinase, 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: 70328.37

構造登録者

Sakai, N.,Mishima-Tsumagari, C.,Matsumoto, T.,Shirouzu, M. (登録日: 2018-07-27, 公開日: 2019-03-20, 最終更新日: 2023-11-22)

主引用文献

Sekimata, K.,Sato, T.,Sakai, N.,Watanabe, H.,Mishima-Tsumagari, C.,Taguri, T.,Matsumoto, T.,Fujii, Y.,Handa, N.,Honma, T.,Tanaka, A.,Shirouzu, M.,Yokoyama, S.,Miyazono, K.,Hashizume, Y.,Koyama, H.
Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H).
Chem. Pharm. Bull., 67:224-235, 2019

PubMed Abstract: Mutant activin receptor-like kinase-2 (ALK2) was reported to be closely associated with the pathogenesis of fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG), and therefore presents an attractive target for therapeutic intervention. Through in silico virtual screenings and structure-activity relationship studies assisted by X-ray crystallographic analyses, a novel series of bis-heteroaryl pyrazole was identified as potent inhibitors of ALK2 (R206H). Derived from in silico hit compound RK-59638 (6a), compound 18p was identified as a potent inhibitor of ALK2 (R206H) with good aqueous solubility, liver microsomal stability, and oral bioavailability.

PubMed: 30828000
DOI: 10.1248/cpb.c18-00598

実験手法

X-RAY DIFFRACTION (2.01 Å)