8C7Z

Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2308

8C7Z の概要

• エントリーDOI: 10.2210/pdb8c7z/pdb
• 分子名称: Activin receptor type I, AMMONIUM ION, 9-piperazin-1-yl-4-(3,4,5-trimethoxyphenyl)-5,6-dihydro-[1]benzoxepino[5,4-c]pyridine, ... (6 entities in total)
• 機能のキーワード: bmp signalling kinase inhibitor, signaling protein
• 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: 36166.26

構造登録者

Cros, J.,Williams, E.P.,Sweeney, M.N.,Smil, D.,Gonzalez-Alvarez, H.,Al-awar, R.,Bullock, A.N. (登録日: 2023-01-18, 公開日: 2023-02-01, 最終更新日: 2024-08-14)

主引用文献

Gonzalez-Alvarez, H.,Ensan, D.,Xin, T.,Wong, J.F.,Zepeda-Velazquez, C.A.,Cros, J.,Sweeney, M.N.,Hoffer, L.,Kiyota, T.,Wilson, B.J.,Aman, A.,Roberts, O.,Isaac, M.B.,Bullock, A.N.,Smil, D.,Al-Awar, R.
Discovery of Conformationally Constrained ALK2 Inhibitors.
J.Med.Chem., 67:4707-4725, 2024

PubMed Abstract: Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made on improving patient outcomes. In this work, we explored novel scaffold modifications of , a 3,5-diphenylpyridine ALK2 inhibitor previously reported by our group. Here we disclose the design, synthesis, and evaluation of a first-in-class set of 5- to 7-membered ether-linked and 7-membered amine-linked constrained inhibitors of ALK2. This rigidification strategy led us to the discovery of the ether-linked inhibitors and and the amine-linked inhibitors and , each with superior potency against ALK2. Notably, and exhibit exceptional selectivity for ALK2 over ALK5, surpassing the reference compound. Preliminary studies on their in vivo pharmacokinetics, including blood-brain barrier penetration, revealed that these constrained scaffolds have favorable exposure and do open a novel chemical space for further optimization and future evaluation in orthotopic models of DIPG.

PubMed: 38498998
DOI: 10.1021/acs.jmedchem.3c02308

実験手法

X-RAY DIFFRACTION (2.23 Å)