| Structural highlights
6szm is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , |
| Gene: | ACVR1 (HUMAN) |
| Activity: | Receptor protein serine/threonine kinase, with EC number 2.7.11.30 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[ACVR1_HUMAN] Fibrodysplasia ossificans progressiva. Defects in ACVR1 are a cause of fibrodysplasia ossificans progressiva (FOP) [MIM:135100]. FOP is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. Heterotopic ossification in FOP begins in childhood and can be induced by trauma or may occur without warning. Bone formation is episodic and progressive, leading to extra-articular ankylosis of all major joints of the axial and appendicular skeleton, rendering movement impossible.[1] [2] [3]
Function
[ACVR1_HUMAN] On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for activin. May be involved for left-right pattern formation during embryogenesis (By similarity).
Publication Abstract from PubMed
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 LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.
Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma.,Smil D, Wong JF, Williams EP, Adamson RJ, Howarth A, McLeod DA, Mamai A, Kim S, Wilson BJ, Kiyota T, Aman A, Owen J, Poda G, Horiuchi KY, Kuznetsova E, Ma H, Hamblin JN, Cramp S, Roberts OG, Edwards AM, Uehling D, Al-Awar R, Bullock AN, O'Meara JA, Isaac MB J Med Chem. 2020 Sep 10;63(17):10061-10085. doi: 10.1021/acs.jmedchem.0c01199., Epub 2020 Aug 26. PMID:32787083[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006 May;38(5):525-7. Epub 2006 Apr 23. PMID:16642017 doi:ng1783
- ↑ Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, Delai P, Fastnacht-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Koster B, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Morhart R, Mundlos S, Groppe J, Shore EM. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat. 2009 Mar;30(3):379-90. doi: 10.1002/humu.20868. PMID:19085907 doi:10.1002/humu.20868
- ↑ Petrie KA, Lee WH, Bullock AN, Pointon JJ, Smith R, Russell RG, Brown MA, Wordsworth BP, Triffitt JT. Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients. PLoS One. 2009;4(3):e5005. doi: 10.1371/journal.pone.0005005. Epub 2009 Mar 30. PMID:19330033 doi:10.1371/journal.pone.0005005
- ↑ Smil D, Wong JF, Williams EP, Adamson RJ, Howarth A, McLeod DA, Mamai A, Kim S, Wilson BJ, Kiyota T, Aman A, Owen J, Poda G, Horiuchi KY, Kuznetsova E, Ma H, Hamblin JN, Cramp S, Roberts OG, Edwards AM, Uehling D, Al-Awar R, Bullock AN, O'Meara JA, Isaac MB. Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma. J Med Chem. 2020 Sep 10;63(17):10061-10085. doi: 10.1021/acs.jmedchem.0c01199., Epub 2020 Aug 26. PMID:32787083 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c01199
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