6SZM
Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2009
Summary for 6SZM
| Entry DOI | 10.2210/pdb6szm/pdb |
| Descriptor | Activin receptor type I, 1-[4-[4-methyl-5-(3,4,5-trimethoxyphenyl)pyridin-3-yl]phenyl]piperazine, SULFATE ION, ... (7 entities in total) |
| Functional Keywords | kinase, bmp, inhibitor, signalling, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 71764.29 |
| 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: 2019-10-02, release date: 2019-10-16, Last modification date: 2024-01-24) |
| Primary citation | 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 Cited by 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: 32787083DOI: 10.1021/acs.jmedchem.0c01199 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.42 Å) |
Structure validation
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