8R7G
Crystal structure of the kinase domain of ACVR1 (ALK2) with M4K2234
Summary for 8R7G
| Entry DOI | 10.2210/pdb8r7g/pdb |
| Descriptor | Activin receptor type I, 2-fluoranyl-6-methoxy-4-[4-methyl-5-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pyridin-3-yl]benzamide (3 entities in total) |
| Functional Keywords | alk2, acvr1, kinase, inhibitor, m4k2234, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 140000.77 |
| Authors | Williams, E.P.,Cros, J.,Ensan, D.,Smil, D.,Edwards, A.M.,O'Meara, J.A.,Fernandez-Cid, A.,Isaac, M.B.,Al-awar, R.,Bullock, A.N. (deposition date: 2023-11-24, release date: 2024-04-03) |
| 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 (2.09 Å) |
Structure validation
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