6SZM

Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2009

6SZM の概要

• エントリーDOI: 10.2210/pdb6szm/pdb
• 分子名称: Activin receptor type I, 1-[4-[4-methyl-5-(3,4,5-trimethoxyphenyl)pyridin-3-yl]phenyl]piperazine, SULFATE ION, ... (7 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: 2
• 化学式量合計: 71764.29

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: 2019-10-02, 公開日: 2019-10-16, 最終更新日: 2024-01-24)

主引用文献

Smil, D.,Wong, J.F.,Williams, E.P.,Adamson, R.J.,Howarth, A.,McLeod, D.A.,Mamai, A.,Kim, S.,Wilson, B.J.,Kiyota, T.,Aman, A.,Owen, J.,Poda, G.,Horiuchi, K.Y.,Kuznetsova, E.,Ma, H.,Hamblin, J.N.,Cramp, S.,Roberts, O.G.,Edwards, A.M.,Uehling, D.,Al-Awar, R.,Bullock, A.N.,O'Meara, J.A.,Isaac, M.B.
Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma.
J.Med.Chem., 63:10061-10085, 2020

PubMed Abstract: There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound . Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds , , and , each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.

PubMed: 32787083
DOI: 10.1021/acs.jmedchem.0c01199

実験手法

X-RAY DIFFRACTION (1.42 Å)