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Insulin-like growth factor I receptor

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Target id: 1801

Nomenclature: Insulin-like growth factor I receptor

Abbreviated Name: IGF1R

Family: Type II RTKs: Insulin receptor family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1367 15q26.3 IGF1R insulin like growth factor 1 receptor
Mouse 1 1373 7 37.27 cM Igf1r insulin-like growth factor I receptor
Rat 1 1370 1q22 Igf1r insulin-like growth factor 1 receptor
Previous and Unofficial Names Click here for help
hyft | CD221 | IGFR | JTK13
Database Links Click here for help
Alphafold P08069 (Hs), Q60751 (Mm), P24062 (Rn)
BRENDA 2.7.10.1
CATH/Gene3D 3.80.20.20, 2.60.40.10
ChEMBL Target CHEMBL1957 (Hs), CHEMBL5381 (Mm), CHEMBL1075098 (Rn)
DrugBank Target P08069 (Hs)
Ensembl Gene ENSG00000140443 (Hs), ENSMUSG00000005533 (Mm), ENSRNOG00000014187 (Rn)
Entrez Gene 3480 (Hs), 16001 (Mm), 25718 (Rn)
Human Protein Atlas ENSG00000140443 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:3480 (Hs), mmu:16001 (Mm), rno:25718 (Rn)
OMIM 147370 (Hs)
Orphanet ORPHA138578 (Hs)
Pharos P08069 (Hs)
RefSeq Nucleotide NM_000875 (Hs), NM_010513 (Mm), NM_052807 (Rn)
RefSeq Protein NP_000866 (Hs), NP_034643 (Mm), NP_434694 (Rn)
SynPHARM 80880 (in complex with BMS-754807)
UniProtKB P08069 (Hs), Q60751 (Mm), P24062 (Rn)
Wikipedia IGF1R (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the Insulin-like Growth Factor 1 Receptor Kinase
PDB Id:  1K3A
Resolution:  2.1Å
Species:  Human
References:  6
Image of receptor 3D structure from RCSB PDB
Description:  Structure of IGF-1R kinase domain complexed with a benzimidazole inhibitor
PDB Id:  2OJ9
Resolution:  2.0Å
Species:  Human
References:  20
Enzyme Reaction Click here for help
EC Number: 2.7.10.1
Natural/Endogenous Ligands Click here for help
insulin-like growth factor 1 {Sp: Human}
insulin-like growth factor 2 {Sp: Human}

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
GSK-1838705A Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.1 pKd 5
⤷ pKd 8.1 (Kd 7x10-9 M) [5]
NVP-AEW541 Small molecule or natural product Primary target of this compound Hs Inhibition 9.4 pIC50 10
⤷ pIC50 9.4 (IC50 4x10-10 M) [10]
picropodophyllin Small molecule or natural product Primary target of this compound Hs Inhibition ~9.0 pIC50 11
⤷ pIC50 ~9.0 (IC50 ~1x10-9 M) [11]
GSK-1838705A Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.7 pIC50 19
⤷ pIC50 8.7 (IC50 2x10-9 M) [19]
BMS-754807 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.7 pIC50 22
⤷ pIC50 8.7 (IC50 2x10-9 M) [22]
ceritinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 15
⤷ pIC50 8.1 (IC50 8x10-9 M) [15]
AZD3463 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition >8.0 pIC50 2
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [2]
brigatinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.6 pIC50 13
⤷ pIC50 7.6 (IC50 2.46x10-8 M) [13]
linsitinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.5 pIC50 16
⤷ pIC50 7.5 (IC50 3.5x10-8 M) [16]
Description: Biochemical enzyme inhibition assay.
BMS-536924 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.0 pIC50 21
⤷ pIC50 7.0 (IC50 1x10-7 M) [21]
NVP-TAE 226 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition ~6.8 pIC50 14
⤷ pIC50 ~6.8 (IC50 ~1.4x10-7 M) [14]
Description: In vitro kinase assay with recombinant kinase domains and peptide substrates.
GSK1511931 Small molecule or natural product Hs Inhibition 6.6 pIC50 4
⤷ pIC50 6.6 (IC50 2.5x10-7 M) [4]
fexagratinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.2 pIC50 3
⤷ pIC50 6.2 (IC50 5.81x10-7 M) [3]
PQ401 Small molecule or natural product Primary target of this compound Hs Inhibition >6.0 pIC50 8
⤷ pIC50 >6.0 (IC50 <1x10-6 M) [8]
compound 19a [PMID: 30503936] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.7 pIC50 18
⤷ pIC50 5.7 (IC50 2.1x10-6 M) [18]
AG 1024 Small molecule or natural product Primary target of this compound Hs Inhibition 4.7 pIC50 17
⤷ pIC50 4.7 (IC50 1.8x10-5 M) [17]
Agonist Comments
Insulin-like growth factor 1 receptor is the primary target of the approved drug mecasermin, a recombinant form of endogenous IGF1.
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
teprotumumab Peptide Approved drug Primary target of this compound Immunopharmacology Ligand Hs Antagonist 9.3 – 12.2 pKd 12
⤷ pKd 12.2 (Kd 6.95x10-13 M) [12]
Description: Dissociation constant for antibody 18; determined by SPR binding analysis using a Biacore assay.
pKd 9.3 (Kd 5.65x10-10 M) [12]
Description: Dissociation constant for antibody 22; determined by SPR binding analysis using a Biacore assay.
istiratumab Peptide Primary target of this compound Click here for species-specific activity table Hs Binding >9.0 pKd 7
⤷ pKd >9.0 (Kd <1x10-9 M) [7]
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: 5,23
Key to terms and symbols Click column headers to sort
Target used in screen: IGF1R
Ligand Sp. Type Action Value Parameter
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.6 pKd
GSK-1838705A Small molecule or natural product Hs Inhibitor Inhibition 8.1 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.1 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.1 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.0 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 6.0 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 5.9 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 5.7 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: 1,9
Key to terms and symbols Click column headers to sort
Target used in screen: IGF-1R (activated)/nd
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 10.0 10.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 14.5 4.0
GSK-3 inhibitor XIII Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 20.0 1.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 23.0 3.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 30.0 3.0
indirubin-3'-monoxime Small molecule or natural product Hs Inhibitor Inhibition 40.0 20.0
isogranulatimide Small molecule or natural product Hs Inhibitor Inhibition 45.0 30.0
purvalanol A Small molecule or natural product Hs Inhibitor Inhibition 48.0 12.0
aloisine Small molecule or natural product Hs Inhibitor Inhibition 61.0 51.0
aloisine A Small molecule or natural product Hs Inhibitor Inhibition 65.0 66.0
Target used in screen: IGF-1R/IGF1R
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.6 109.0 98.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 14.8 92.5 6.5
Cdk4 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 15.0 87.0 91.0
Cdk/Crk inhibitor Small molecule or natural product Hs Inhibitor Inhibition 24.8 135.0 103.0
Cdk2 inhibitor IV Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 28.4 120.0 114.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 35.2 135.0 13.0
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 39.1 25.0 2.0
CGP74514A Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 51.8 95.0 123.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 57.2 77.0 14.0
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 62.6
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Insulin-like growth factor I, resistance to
Synonyms: Growth delay due to insulin-like growth factor I resistance [Orphanet: ORPHA73273]
OMIM: 270450
Orphanet: ORPHA73273

References

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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. AstraZeneca. AZD3463. Accessed on 11/09/2014. Modified on 11/09/2014. astrazeneca.com, http://openinnovation.astrazeneca.com/what-we-offer/compound/azd3463/

3. AstraZeneca. AZD4547. Accessed on 11/09/2014. Modified on 11/09/2014. astrazeneca.com, http://openinnovation.astrazeneca.com/what-we-offer/compound/azd4547/

4. Chamberlain SD, Redman AM, Patnaik S, Brickhouse K, Chew YC, Deanda F, Gerding R, Lei H, Moorthy G, Patrick M et al.. (2009) Optimization of a series of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine inhibitors of IGF-1R: elimination of an acid-mediated decomposition pathway. Bioorg Med Chem Lett, 19 (2): 373-7. [PMID:19081716]

5. 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]

6. Favelyukis S, Till JH, Hubbard SR, Miller WT. (2001) Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat Struct Biol, 8 (12): 1058-63. [PMID:11694888]

7. Fitzgerald JB, Johnson BW, Baum J, Adams S, Iadevaia S, Tang J, Rimkunas V, Xu L, Kohli N, Rennard R et al.. (2014) MM-141, an IGF-IR- and ErbB3-directed bispecific antibody, overcomes network adaptations that limit activity of IGF-IR inhibitors. Mol Cancer Ther, 13 (2): 410-25. [PMID:24282274]

8. Gable KL, Maddux BA, Penaranda C, Zavodovskaya M, Campbell MJ, Lobo M, Robinson L, Schow S, Kerner JA, Goldfine ID et al.. (2006) Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth. Mol Cancer Ther, 5 (4): 1079-86. [PMID:16648580]

9. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

10. García-Echeverría C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, Gao J, Brueggen J, Capraro HG, Cozens R et al.. (2004) In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell, 5 (3): 231-9. [PMID:15050915]

11. Girnita A, Girnita L, del Prete F, Bartolazzi A, Larsson O, Axelson M. (2004) Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth. Cancer Res, 64 (1): 236-42. [PMID:14729630]

12. Graus Y, Kopetzki E, Kuenkele K-P, Mundigl O, Parren P, Rebers F, Schumacher R, Van De Winkel J, Van Vugt M. (2005) Antibodies against insulin-like growth factor i receptor and uses thereof. Patent number: WO2005005635A2. Assignee: Hoffmann-La Roche Ag. Priority date: 10/07/2003. Publication date: 20/01/2005.

13. Huang WS, Liu S, Zou D, Thomas M, Wang Y, Zhou T, Romero J, Kohlmann A, Li F, Qi J et al.. (2016) Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. J Med Chem, 59 (10): 4948-64. [PMID:27144831]

14. Liu TJ, LaFortune T, Honda T, Ohmori O, Hatakeyama S, Meyer T, Jackson D, de Groot J, Yung WK. (2007) Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol Cancer Ther, 6 (4): 1357-67. [PMID:17431114]

15. Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, Jiang T, Kim S, Li N, Warmuth M et al.. (2013) Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem, 56 (14): 5675-90. [PMID:23742252]

16. Mulvihill MJ, Cooke A, Rosenfeld-Franklin M, Buck E, Foreman K, Landfair D, O'Connor M, Pirritt C, Sun Y, Yao Y et al.. (2009) Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med Chem, 1 (6): 1153-71. [PMID:21425998]

17. Párrizas M, Gazit A, Levitzki A, Wertheimer E, LeRoith D. (1997) Specific inhibition of insulin-like growth factor-1 and insulin receptor tyrosine kinase activity and biological function by tyrphostins. Endocrinology, 138 (4): 1427-33. [PMID:9075698]

18. Qi B, Yang Y, Gong G, He H, Yue X, Xu X, Hu Y, Li J, Chen T, Wan X et al.. (2019) Discovery of N1-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-N3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)urea as a multi-tyrosine kinase inhibitor for drug-sensitive and drug-resistant cancers treatment. Eur J Med Chem, 163: 10-27. [PMID:30503936]

19. Sabbatini P, Korenchuk S, Rowand JL, Groy A, Liu Q, Leperi D, Atkins C, Dumble M, Yang J, Anderson K et al.. (2009) GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. Mol Cancer Ther, 8 (10): 2811-20. [PMID:19825801]

20. Velaparthi U, Wittman M, Liu P, Stoffan K, Zimmermann K, Sang X, Carboni J, Li A, Attar R, Gottardis M et al.. (2007) Discovery and initial SAR of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-ones as inhibitors of insulin-like growth factor 1-receptor (IGF-1R). Bioorg Med Chem Lett, 17 (8): 2317-21. [PMID:17317169]

21. Wittman M, Carboni J, Attar R, Balasubramanian B, Balimane P, Brassil P, Beaulieu F, Chang C, Clarke W, Dell J et al.. (2005) Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity. J Med Chem, 48 (18): 5639-43. [PMID:16134929]

22. Wittman MD, Carboni JM, Yang Z, Lee FY, Antman M, Attar R, Balimane P, Chang C, Chen C, Discenza L et al.. (2009) Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development. J Med Chem, 52 (23): 7360-3. [PMID:19778024]

23. 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 II RTKs: Insulin receptor family: Insulin-like growth factor I receptor. Last modified on 22/01/2020. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1801.