6T6D

Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2149

6T6D の概要

• エントリーDOI: 10.2210/pdb6t6d/pdb
• 分子名称: Activin receptor type I, 2-methoxy-4-[4-methyl-5-(4-piperazin-1-ylphenyl)pyridin-3-yl]benzamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: kinase, bmp, inhibitor, signalling, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 140817.18

構造登録者

Adamson, R.J.,Williams, E.P.,Smil, D.,Burgess-Brown, N.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Bullock, A.N. (登録日: 2019-10-18, 公開日: 2019-10-30, 最終更新日: 2024-10-23)

主引用文献

Ensan, D.,Smil, D.,Zepeda-Velazquez, C.A.,Panagopoulos, D.,Wong, J.F.,Williams, E.P.,Adamson, R.,Bullock, A.N.,Kiyota, T.,Aman, A.,Roberts, O.G.,Edwards, A.M.,O'Meara, J.A.,Isaac, M.B.,Al-Awar, R.
Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma.
J.Med.Chem., 63:4978-4996, 2020

PubMed Abstract: Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of , an analogue of the previously reported ALK2 inhibitor . Although highly selective for ALK2 over the TGF-βR1 receptor ALK5, is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.

PubMed: 32369358
DOI: 10.1021/acs.jmedchem.0c00395

実験手法

X-RAY DIFFRACTION (2.56 Å)