8C7Z
Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2308
Summary for 8C7Z
| Entry DOI | 10.2210/pdb8c7z/pdb |
| Descriptor | 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) |
| Functional Keywords | bmp signalling kinase inhibitor, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 36166.26 |
| Authors | Cros, J.,Williams, E.P.,Sweeney, M.N.,Smil, D.,Gonzalez-Alvarez, H.,Al-awar, R.,Bullock, A.N. (deposition date: 2023-01-18, release date: 2023-02-01, Last modification date: 2024-08-14) |
| Primary citation | 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 Cited by 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: 38498998DOI: 10.1021/acs.jmedchem.3c02308 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.23 Å) |
Structure validation
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