Insulin-like growth factor I receptor | Type II RTKs: Insulin receptor family | IUPHAR/BPS Guide to PHARMACOLOGY

Top ▲

Insulin-like growth factor I receptor

Target not currently curated in GtoImmuPdb

Target id: 1801

Nomenclature: Insulin-like growth factor I receptor

Abbreviated Name: IGF1R

Family: Type II RTKs: Insulin receptor family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1367 15q26.3 IGF1R insulin like growth factor 1 receptor
Mouse 1 1369 7 Igf1r insulin-like growth factor I receptor
Rat 1 1370 1q22 Igf1r insulin-like growth factor 1 receptor
Previous and Unofficial Names
hyft | CD221 | IGFR | JTK13
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
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:  19
Enzyme Reaction
EC Number: 2.7.10.1
Natural/Endogenous Ligands
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

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
GSK-1838705A Hs Inhibition 8.1 pKd 5
pKd 8.1 (Kd 7x10-9 M) [5]
NVP-AEW541 Hs Inhibition 9.4 pIC50 10
pIC50 9.4 (IC50 4x10-10 M) [10]
picropodophyllin Hs Inhibition ~9.0 pIC50 11
pIC50 ~9.0 (IC50 ~1x10-9 M) [11]
GSK-1838705A Hs Inhibition 8.7 pIC50 18
pIC50 8.7 (IC50 2x10-9 M) [18]
BMS-754807 Hs Inhibition 8.7 pIC50 21
pIC50 8.7 (IC50 2x10-9 M) [21]
ceritinib Hs Inhibition 8.1 pIC50 14
pIC50 8.1 (IC50 8x10-9 M) [14]
AZD3463 Hs Inhibition >8.0 pIC50 2
pIC50 >8.0 (IC50 <1x10-8 M) [2]
brigatinib Hs Inhibition 7.6 pIC50 12
pIC50 7.6 (IC50 2.46x10-8 M) [12]
linsitinib Hs Inhibition 7.5 pIC50 15
pIC50 7.5 (IC50 3.5x10-8 M) [15]
Description: Biochemical enzyme inhibition assay.
BMS-536924 Hs Inhibition 7.0 pIC50 20
pIC50 7.0 (IC50 1x10-7 M) [20]
NVP-TAE 226 Hs Inhibition ~6.8 pIC50 13
pIC50 ~6.8 (IC50 ~1.4x10-7 M) [13]
Description: In vitro kinase assay with recombinant kinase domains and peptide substrates.
GSK1511931 Hs Inhibition 6.6 pIC50 4
pIC50 6.6 (IC50 2.5x10-7 M) [4]
AZD4547 Hs Inhibition 6.2 pIC50 3
pIC50 6.2 (IC50 5.81x10-7 M) [3]
PQ401 Hs Inhibition >6.0 pIC50 8
pIC50 >6.0 (IC50 <1x10-6 M) [8]
compound 19a [PMID: 30503936] Hs Inhibition 5.7 pIC50 17
pIC50 5.7 (IC50 2.1x10-6 M) [17]
AG 1024 Hs Inhibition 4.7 pIC50 16
pIC50 4.7 (IC50 1.8x10-5 M) [16]
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
istiratumab Hs Binding >9.0 pKd 7
pKd >9.0 (Kd <1x10-9 M) [7]
DiscoveRx KINOMEscan® screen
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: 5,22

Key to terms and symbols Click column headers to sort
Target used in screen: IGF1R
Ligand Sp. Type Action Value Parameter
NVP-TAE684 Hs Inhibitor Inhibition 8.6 pKd
GSK-1838705A Hs Inhibitor Inhibition 8.1 pKd
staurosporine Hs Inhibitor Inhibition 6.7 pKd
foretinib Hs Inhibitor Inhibition 6.4 pKd
tozasertib Hs Inhibitor Inhibition 6.1 pKd
crizotinib Hs Inhibitor Inhibition 6.1 pKd
KW-2449 Hs Inhibitor Inhibition 6.0 pKd
JNJ-28312141 Hs Inhibitor Inhibition 6.0 pKd
tamatinib Hs Inhibitor Inhibition 5.9 pKd
fedratinib 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
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 Hs Inhibitor Inhibition 10.0 10.0
staurosporine Hs Inhibitor Inhibition 14.5 4.0
GSK-3 inhibitor XIII Hs Inhibitor Inhibition 20.0 1.0
K-252a Hs Inhibitor Inhibition 23.0 3.0
SU11652 Hs Inhibitor Inhibition 30.0 3.0
indirubin-3'-monoxime Hs Inhibitor Inhibition 40.0 20.0
isogranulatimide Hs Inhibitor Inhibition 45.0 30.0
purvalanol A Hs Inhibitor Inhibition 48.0 12.0
aloisine Hs Inhibitor Inhibition 61.0 51.0
IKK-2 inhibitor IV Hs Inhibitor Inhibition 65.0 19.0
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 Hs Inhibitor Inhibition 0.6 109.0 98.0
staurosporine Hs Inhibitor Inhibition 14.8 92.5 6.5
Cdk4 inhibitor Hs Inhibitor Inhibition 15.0 87.0 91.0
Cdk/Crk inhibitor Hs Inhibitor Inhibition 24.8 135.0 103.0
Cdk2 inhibitor IV Hs Inhibitor Inhibition 28.4 120.0 114.0
SU11652 Hs Inhibitor Inhibition 35.2 135.0 13.0
indirubin derivative E804 Hs Inhibitor Inhibition 39.1 25.0 2.0
CGP74514A Hs Inhibitor Inhibition 51.8 95.0 123.0
K-252a Hs Inhibitor Inhibition 57.2 77.0 14.0
sunitinib Hs Inhibitor Inhibition 62.6
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
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

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. 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. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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]

22. 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 16/01/2019. Accessed on 21/11/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1801.