6T6D
Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2149
Summary for 6T6D
| Entry DOI | 10.2210/pdb6t6d/pdb |
| Descriptor | Activin receptor type I, 2-methoxy-4-[4-methyl-5-(4-piperazin-1-ylphenyl)pyridin-3-yl]benzamide, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | kinase, bmp, inhibitor, signalling, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 140817.18 |
| Authors | 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. (deposition date: 2019-10-18, release date: 2019-10-30, Last modification date: 2024-10-23) |
| Primary citation | 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 Cited by 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: 32369358DOI: 10.1021/acs.jmedchem.0c00395 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.56 Å) |
Structure validation
Download full validation report
