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activin A receptor type 1

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Target id: 1785

Nomenclature: activin A receptor type 1

Abbreviated Name: ALK2

Family: Type I receptor serine/threonine kinases

Contents:

Quaternary Structure: Complexes
Bone morphogenetic protein receptors
Anti-Müllerian hormone receptors
Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 509 2q24.1 ACVR1 activin A receptor type 1
Mouse 1 509 2 C1.1 Acvr1 activin A receptor, type 1
Rat 1 509 3q21 Acvr1 activin A receptor type 1
Previous and Unofficial Names Click here for help
activin A receptor | activin A receptor, type I | activin A receptor type I | ACTRI | ACVR1A | Acvrlk2 | ACVRLK2 | Alk-2 | Alk8 | serine/threonine-protein kinase receptor R1 | SKR1 | TGF-B superfamily receptor type I | TSK-7L | TSR-I
Database Links Click here for help
Alphafold Q04771 (Hs), P37172 (Mm), P80201 (Rn)
BRENDA 2.7.11.30
ChEMBL Target CHEMBL5903 (Hs), CHEMBL3309042 (Mm)
Ensembl Gene ENSG00000115170 (Hs), ENSMUSG00000026836 (Mm), ENSRNOG00000005033 (Rn)
Entrez Gene 90 (Hs), 11477 (Mm), 79558 (Rn)
Human Protein Atlas ENSG00000115170 (Hs)
KEGG Enzyme 2.7.11.30
KEGG Gene hsa:90 (Hs), mmu:11477 (Mm), rno:79558 (Rn)
OMIM 102576 (Hs)
Orphanet ORPHA117759 (Hs)
Pharos Q04771 (Hs)
RefSeq Nucleotide NM_001105 (Hs), NM_001110205 (Mm), NM_024486 (Rn)
RefSeq Protein NP_001096 (Hs), NP_001103675 (Mm), NP_001103674 (Mm), NP_031420 (Mm), NP_077812 (Rn)
UniProtKB Q04771 (Hs), P37172 (Mm), P80201 (Rn)
Wikipedia ACVR1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the kinase domain of type I activin receptor (ACVR1) in complex with FKBP12 and dorsomorphin
PDB Id:  3H9R
Resolution:  2.35Å
Species:  Human
References:  5
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the ACVR1 (ALK2) kinase in complex with cyclical inhibitor OD36.
PDB Id:  5OY6
Ligand:  OD36
Resolution:  2.56Å
Species:  Human
References: 
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the ACVR1 kinase (ALK2) in complex with a 2-aminopyridine inhibitor
PDB Id:  3MTF
Ligand:  K02288
Resolution:  2.15Å
Species:  Human
References:  11
Enzyme Reaction Click here for help
EC Number: 2.7.11.30

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
K02288 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.0 pIC50 13
⤷ pIC50 9.0 (IC50 1.1x10-9 M) [13]
compound 13d [PMID: 23639540] Small molecule or natural product Click here for species-specific activity table Hs Inhibition >8.3 pIC50 7
⤷ pIC50 >8.3 (IC50 <5x10-9 M) [7]
compound 13r [PMID: 23639540] Small molecule or natural product Click here for species-specific activity table Hs Inhibition >8.3 pIC50 7
⤷ pIC50 >8.3 (IC50 <5x10-9 M) [7]
momelotinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 3
⤷ pIC50 8.1 (IC50 8.4x10-9 M) [3]
itacnosertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >8.0 pIC50 9
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [9]
Description: Inhibitory activity against human AKL2, determined using a LanthaScreen® binding assay.
fidrisertib Small molecule or natural product Hs Inhibition >8.0 pIC50 4
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [4]
zilurgisertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pIC50 2
⤷ pIC50 7.6 (IC50 2.3x10-8 M) [2]
LDN-214117 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.6 pIC50 8
⤷ pIC50 7.6 (IC50 2.4x10-8 M) [8]
ML347 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.5 pIC50 7
⤷ pIC50 7.5 (IC50 3.2x10-8 M) [7]
compound 13a [PMID: 23639540] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.3 pIC50 7
⤷ pIC50 7.3 (IC50 5.34x10-8 M) [7]
BMS-986260 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.2 pIC50 12
⤷ pIC50 7.2 (IC50 7.04x10-8 M) [12]
compound 7 [Nguyen et al., 2023] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.0 pIC50 10
⤷ pIC50 6.0 (IC50 9.3x10-7 M) [10]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 6,14
Key to terms and symbols Click column headers to sort
Target used in screen: ACVR1
Ligand Sp. Type Action Value Parameter
PP-242 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.4 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.5 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.1 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.8 pKd
vandetanib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.8 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.8 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.8 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 6.4 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.4 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: ...1
Key to terms and symbols Click column headers to sort
Target used in screen: nd/ALK2(ACVR1)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
dorsomorphin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 15.4
alsterpaullone 2-cyanoethyl Small molecule or natural product Hs Inhibitor Inhibition 58.8
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 60.4
JNK inhibitor IX Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 72.9
PQ401 Small molecule or natural product Hs Inhibitor Inhibition 76.2
alsterpaullone Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 79.7
compound 52 [PMID: 9677190] Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 80.3
aloisine A Small molecule or natural product Hs Inhibitor Inhibition 83.8
D4476 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 85.7
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 85.8
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Fibrodysplasia ossificans progressiva
Disease Ontology: DOID:13374
OMIM: 135100
Orphanet: ORPHA337

References

Show »

1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Arista L, Babu S, Bian J, Cui K, Dillon MP, Lattmann R, Li J, Liao L, Lizos D, Ramos R et al.. (2021) Aminopyridine derivatives and their use as selective alk-2 inhibitors. Patent number: US20210155606A1. Assignee: Novartis AG. Priority date: 20/07/2016. Publication date: 27/05/2021.

3. Asshoff M, Petzer V, Warr MR, Haschka D, Tymoszuk P, Demetz E, Seifert M, Posch W, Nairz M, Maciejewski P et al.. (2017) Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood, 129 (13): 1823-1830. [PMID:28188131]

4. Brooijmans N, Brubaker JD, Fleming PE, Hodous BL, Kim JL, Waetzig J, Williams B, Wilson D, Wilson KJ, Cronin M. (2017) Inhibitors of activin receptor-like kinase. Patent number: WO2017181117A1. Assignee: Blueprint Medicines. Priority date: 15/04/2016. Publication date: 19/10/2017.

5. Chaikuad A, Alfano I, Kerr G, Sanvitale CE, Boergermann JH, Triffitt JT, von Delft F, Knapp S, Knaus P, Bullock AN. (2012) Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva. J Biol Chem, 287 (44): 36990-8. [PMID:22977237]

6. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

7. Engers DW, Frist AY, Lindsley CW, Hong CC, Hopkins CR. (2013) Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe. Bioorg Med Chem Lett, 23 (11): 3248-52. [PMID:23639540]

8. Mohedas AH, Wang Y, Sanvitale CE, Canning P, Choi S, Xing X, Bullock AN, Cuny GD, Yu PB. (2014) Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants. J Med Chem, 57 (19): 7900-15. [PMID:25101911]

9. Mollard A, Warner SL, Flymm GA, Vankayalapati H, Bearss DJ. (2014) Jak2 and alk2 inhibitors and methods for their use. Patent number: WO2014151871A9. Assignee: Tolero Pharmaceuticals, Inc.. Priority date: 14/03/2013. Publication date: 31/12/2014.

10. Nguyen MH, Ye HF, Xu Y, Truong L, Horsey A, Styduhar ED, Frascella M, Leffet L, Federowicz K, Behshad E et al.. (2023) Discovery of Orally Bioavailable FGFR2/FGFR3 Dual Inhibitors via Structure-Guided Scaffold Repurposing Approach. ACS Medicinal Chemistry Letters, 14 (3): 312–318. DOI: 10.1021/acsmedchemlett.3c00003

11. Sanvitale CE, Kerr G, Chaikuad A, Ramel MC, Mohedas AH, Reichert S, Wang Y, Triffitt JT, Cuny GD, Yu PB et al.. (2013) A new class of small molecule inhibitor of BMP signaling. PLoS One, 8 (4): e62721. [PMID:23646137]

12. Velaparthi U, Darne CP, Warrier J, Liu P, Rahaman H, Augustine-Rauch K, Parrish K, Yang Z, Swanson J, Brown J et al.. (2020) Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGFβR1 Inhibitor as an Immuno-oncology Agent. ACS Med Chem Lett, 11 (2): 172-178. DOI: 10.1021/acsmedchemlett.9b00552 [PMID:32071685]

13. Witten MR, Wu L, Lai CT, Kapilashrami K, Pusey M, Gallagher K, Chen Y, Yao W. (2022) Inhibition of ALK2 with bicyclic pyridyllactams. Bioorg Med Chem Lett, 55: 128452. [PMID:34780900]

14. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

How to cite this page

Type I receptor serine/threonine kinases: activin A receptor type 1. Last modified on 19/03/2024. Accessed on 03/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1785.