Target Information

Target General Information

Target ID

T48069 (Former ID: TTDS00269)

Target Name

Insulin-like growth factor I receptor (IGF1R)

Synonyms

Type 1 insulin-like growth factor receptor; Insulin-like growth factor 1 receptor; IGF-IR; IGF-I receptor; IGF-1R; IGF-1 receptor; CD221 antigen; CD221

Gene Name

IGF1R

Target Type

Successful target

[1]

Disease

[+] 3 Target-related Diseases

Multiple structural anomalies syndrome [ICD-11: LD2F]

Pituitary gland disorder [ICD-11: 5A60-5A61]

Thyrotoxicosis [ICD-11: 5A02]

Function

Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R. Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1).

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BioChemical Class

Kinase

UniProt ID

IGF1R_HUMAN

EC Number

EC 2.7.10.1

Sequence

MKSGSGGGSPTSLWGLLFLSAALSLWPTSGEICGPGIDIRNDYQQLKRLENCTVIEGYLH
ILLISKAEDYRSYRFPKLTVITEYLLLFRVAGLESLGDLFPNLTVIRGWKLFYNYALVIF
EMTNLKDIGLYNLRNITRGAIRIEKNADLCYLSTVDWSLILDAVSNNYIVGNKPPKECGD
LCPGTMEEKPMCEKTTINNEYNYRCWTTNRCQKMCPSTCGKRACTENNECCHPECLGSCS
APDNDTACVACRHYYYAGVCVPACPPNTYRFEGWRCVDRDFCANILSAESSDSEGFVIHD
GECMQECPSGFIRNGSQSMYCIPCEGPCPKVCEEEKKTKTIDSVTSAQMLQGCTIFKGNL
LINIRRGNNIASELENFMGLIEVVTGYVKIRHSHALVSLSFLKNLRLILGEEQLEGNYSF
YVLDNQNLQQLWDWDHRNLTIKAGKMYFAFNPKLCVSEIYRMEEVTGTKGRQSKGDINTR
NNGERASCESDVLHFTSTTTSKNRIIITWHRYRPPDYRDLISFTVYYKEAPFKNVTEYDG
QDACGSNSWNMVDVDLPPNKDVEPGILLHGLKPWTQYAVYVKAVTLTMVENDHIRGAKSE
ILYIRTNASVPSIPLDVLSASNSSSQLIVKWNPPSLPNGNLSYYIVRWQRQPQDGYLYRH
NYCSKDKIPIRKYADGTIDIEEVTENPKTEVCGGEKGPCCACPKTEAEKQAEKEEAEYRK
VFENFLHNSIFVPRPERKRRDVMQVANTTMSSRSRNTTAADTYNITDPEELETEYPFFES
RVDNKERTVISNLRPFTLYRIDIHSCNHEAEKLGCSASNFVFARTMPAEGADDIPGPVTW
EPRPENSIFLKWPEPENPNGLILMYEIKYGSQVEDQRECVSRQEYRKYGGAKLNRLNPGN
YTARIQATSLSGNGSWTDPVFFYVQAKTGYENFIHLIIALPVAVLLIVGGLVIMLYVFHR
KRNNSRLGNGVLYASVNPEYFSAADVYVPDEWEVAREKITMSRELGQGSFGMVYEGVAKG
VVKDEPETRVAIKTVNEAASMRERIEFLNEASVMKEFNCHHVVRLLGVVSQGQPTLVIME
LMTRGDLKSYLRSLRPEMENNPVLAPPSLSKMIQMAGEIADGMAYLNANKFVHRDLAARN
CMVAEDFTVKIGDFGMTRDIYETDYYRKGGKGLLPVRWMSPESLKDGVFTTYSDVWSFGV
VLWEIATLAEQPYQGLSNEQVLRFVMEGGLLDKPDNCPDMLFELMRMCWQYNPKMRPSFL
EIISSIKEEMEPGFREVSFYYSEENKLPEPEELDLEPENMESVPLDPSASSSSLPLPDRH
SGHKAENGPGPGVLVLRASFDERQPYAHMNGGRKNERALPLPQSSTC

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3D Structure

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PDB

HIT2.0 ID

T42XY2

Drugs and Modes of Action

Top

Approved Drug(s)

[+] 3 Approved Drugs

Mecasermin

Drug Info

Approved

Growth failure

[2], [3]

Somatomedin-1

Drug Info

Approved

Hormone deficiency

[4]

Teprotumumab

Drug Info

Approved

Graves disease

[5]

Clinical Trial Drug(s)

[+] 15 Clinical Trial Drugs

OSI-906

Drug Info

Phase 3

Solid tumour/cancer

[6], [7]

Rinfabate

Drug Info

Phase 2/3

Solid tumour/cancer

[8]

AMG 479

Drug Info

Phase 2

Breast cancer

[9]

AXL-1717

Drug Info

Phase 2

Solid tumour/cancer

[10], [11]

Cixutumumab

Drug Info

Phase 2

Non-small-cell lung cancer

[12]

MM-141

Drug Info

Phase 2

Solid tumour/cancer

[13]

R1507

Drug Info

Phase 2

Graves ophthalmopathy

[14]

TT-100

Drug Info

Phase 2

Non-small-cell lung cancer

[15]

VPI-2690B

Drug Info

Phase 2

Diabetic nephropathy

[16]

AEW-541

Drug Info

Phase 1

Multiple myeloma

[17]

BIIB 022

Drug Info

Phase 1

Non-small-cell lung cancer

[18]

Cyclolignan picropodophyllin

Drug Info

Phase 1

Colorectal cancer

[19]

FPI-1434

Drug Info

Phase 1

Solid tumour/cancer

[20]

HF-0299

Drug Info

Phase 1

Pain

[21]

RG-7010

Drug Info

Phase 1

Motor neurone disease

[22]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

AVE-1642

Drug Info

Discontinued in Phase 2

Breast cancer

[23]

KW-2450

Drug Info

Discontinued in Phase 1/2

Breast cancer

[24]

Figitumumab

Drug Info

Discontinued in Phase 1

Malignant adrenal gland cancer

[25]

Preclinical Drug(s)

[+] 2 Preclinical Drugs

BMS-695735

Drug Info

Preclinical

Solid tumour/cancer

[26]

EGFR/IGFR tandem adnectin

Drug Info

Preclinical

Solid tumour/cancer

[27]

Mode of Action

[+] 3 Modes of Action

Inhibitor

[+] 19 Inhibitor drugs

Mecasermin

Drug Info

[1], [28], [29], [30]

OSI-906

Drug Info

[31]

AMG 479

Drug Info

[33], [34]

AXL-1717

Drug Info

[35]

R1507

Drug Info

[38], [39]

TT-100

Drug Info

[40]

AEW-541

Drug Info

[41], [42], [43]

Cyclolignan picropodophyllin

Drug Info

[45]

Figitumumab

Drug Info

[50], [51]

BMS-695735

Drug Info

[52]

EGFR/IGFR tandem adnectin

Drug Info

[53]

4-((1H-indazol-6-ylamino)methyl)benzene-1,2-diol

Drug Info

[54]

4-((naphthalen-2-ylamino)methyl)benzene-1,2-diol

Drug Info

[54]

Alpha-D-Mannose

Drug Info

[55]

AMP-PNP

Drug Info

[56]

BMS-536924

Drug Info

[57]

Fucose

Drug Info

[55]

JB-1

Drug Info

[58]

NVP-ADW742

Drug Info

[58]

Modulator

[+] 7 Modulator drugs

Somatomedin-1

Drug Info

[3]

Rinfabate

Drug Info

[32]

Cixutumumab

Drug Info

[36]

MM-141

Drug Info

[37]

HF-0299

Drug Info

[21]

RG-7010

Drug Info

[47]

KW-2450

Drug Info

[49]

Antagonist

[+] 3 Antagonist drugs

Teprotumumab

Drug Info

[5]

VPI-2690B

Drug Info

[16]

BIIB 022

Drug Info

[44]

Chemical Structure based Activity Landscape of Target

Top

Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

Top

Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 20 KEGG Pathways	+
1	Ras signaling pathway
2	Rap1 signaling pathway
3	HIF-1 signaling pathway
4	FoxO signaling pathway
5	Oocyte meiosis
6	Endocytosis
7	PI3K-Akt signaling pathway
8	AMPK signaling pathway
9	Focal adhesion
10	Adherens junction
11	Signaling pathways regulating pluripotency of stem cells
12	Long-term depression
13	Ovarian steroidogenesis
14	Progesterone-mediated oocyte maturation
15	Pathways in cancer
16	Transcriptional misregulation in cancer
17	Proteoglycans in cancer
18	Glioma
19	Prostate cancer
20	Melanoma
Panther Pathway	[+] 2 Panther Pathways	+
1	Insulin/IGF pathway-mitogen activated protein kinase kinase/MAP kinase cascade
2	Insulin/IGF pathway-protein kinase B signaling cascade
PID Pathway	[+] 6 PID Pathways	+
1	Plasma membrane estrogen receptor signaling
2	SHP2 signaling
3	IGF1 pathway
4	Posttranslational regulation of adherens junction stability and dissassembly
5	Integrins in angiogenesis
6	Stabilization and expansion of the E-cadherin adherens junction
Reactome	[+] 2 Reactome Pathways	+
1	IRS-related events triggered by IGF1R
2	SHC-related events triggered by IGF1R
WikiPathways	[+] 9 WikiPathways	+
1	Senescence and Autophagy in Cancer
2	Insulin Signaling
3	Endochondral Ossification
4	Focal Adhesion
5	Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
6	Apoptosis
7	Signaling Pathways in Glioblastoma
8	TSH signaling pathway
9	MicroRNAs in cardiomyocyte hypertrophy

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

References

Top

REF 1

IGF-1R, IGF-1 and IGF-2 expression as potential prognostic and predictive markers in colorectal-cancer. Virchows Arch. 2003 Aug;443(2):139-45.

REF 2

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 3

2005 approvals: Safety first. Nature Reviews Drug Discovery 5, 92-93 (February 2006).

REF 4

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 5

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020

REF 6

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7423).

REF 7

ClinicalTrials.gov (NCT00924989) A Study of OSI-906 in Patients With Locally Advanced or Metastatic Adrenocortical Carcinoma. U.S. National Institutes of Health.

REF 8

ClinicalTrials.gov (NCT00368173) IGF-I/IGFBP-3 Therapy in Children and Adolescents With Growth Hormone Insenitivity Syndrome (GHIS) Such as Laron Syndrome. U.S. National Institutes of Health.

REF 9

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024318)

REF 10

REF 11

ClinicalTrials.gov (NCT01561456) Study of AXL1717 Compared to Docetaxel to Treat Squamous Cell Carcinoma or Adenocarcinoma of the Lung. U.S. National Institutes of Health.

REF 12

ClinicalTrials.gov (NCT01232452) A Study in Non-Small Cell Lung Cancer. U.S. National Institutes of Health.

REF 13

ClinicalTrials.gov (NCT02399137) A Phase 2 Study of MM-141 Plus Nab-paclitaxel and Gemcitabine in Front-line Metastatic Pancreatic Cancer. U.S. National Institutes of Health.

REF 14

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015801)

REF 15

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021633)

REF 16

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 17

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019974)

REF 18

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027382)

REF 19

Potent inhibitory effect of the cyclolignan picropodophyllin (PPP) on human adrenocortical carcinoma cells proliferation. Am J Cancer Res. 2011; 1(3): 356-361.

REF 20

ClinicalTrials.gov (NCT03746431) A Phase 1 Study of [225Ac]-FPI-1434 Injection. U.S. National Institutes of Health.

REF 21

A primary adrenal steroid, 11beta-hydroxyandrostenedione, has an osteotropic effect and little androgenic activity. J Steroid Biochem Mol Biol. 2000 Nov 15;74(4):203-11.

REF 22

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031207)

REF 23

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021953)

REF 24

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030562)

REF 25

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020634)

REF 26

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022289)

REF 27

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026610)

REF 28

One of two chondrocyte-expressed isoforms of cartilage intermediate-layer protein functions as an insulin-like growth factor 1 antagonist. Arthritis Rheum. 2003 May;48(5):1302-14.

REF 29

Analysis of the human type I insulin-like growth factor receptor promoter region. Biochem Biophys Res Commun. 1991 Jun 28;177(3):1113-20.

REF 30

Insulin-like growth factor I receptor gene structure. J Biol Chem. 1992 May 25;267(15):10759-63.

REF 31

Imidazo[2,1-b]thiazoles: multitargeted inhibitors of both the insulin-like growth factor receptor and members of the epidermal growth factor family... Bioorg Med Chem Lett. 2010 Apr 15;20(8):2452-5.

REF 32

Mecasermin rinfabate: insulin-like growth factor-I/insulin-like growth factor binding protein-3, mecaserimin rinfibate, rhIGF-I/rhIGFBP-3. Drugs R D. 2005;6(2):120-7.

REF 33

Clinical pipeline report, company report or official report of Amgen (2009).

REF 34

AMG 479, a fully human anti-insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinom... Mol Cancer Ther. 2009 May;8(5):1095-105.

REF 35

Clinical Phase I study with an Insulin-like Growth Factor-1 receptor inhibitor: experiences in patients with squamous non-small cell lung carcinoma. Acta Oncol. 2011 Apr;50(3):441-7.

REF 36

Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model. Ann Oncol. 2015 Jul;26(7):1459-64.

REF 37

MM-141, an IGF-IR- and ErbB3-directed bispecific antibody, overcomes network adaptations that limit activity of IGF-IR inhibitors. Mol Cancer Ther. 2014 Feb;13(2):410-25.

REF 38

Clinical pipeline report, company report or official report of Roche (2009).

REF 39

National Cancer Institute. Dictionary of Cancer Terms. 2009.

REF 40

BiPar Sciences Co-founder Reunites Management Team At TriAct Therapeutics to Advance Clinical Stage Cancer Programs. TriAct Therapeutics. Sept. 10, 2009.

REF 41

A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.

REF 42

Co-targeting the EGFR and IGF-IR with anti-EGFR monoclonal antibody ICR62 and the IGF-IR tyrosine kinase inhibitor NVP-AEW541 in colorectal cancer cells. Int J Oncol. 2008 Nov;33(5):1107-13.

REF 43

FAK and IGF-IR interact to provide survival signals in human pancreatic adenocarcinoma cells. Carcinogenesis. 2008 Jun;29(6):1096-107.

REF 44

A phase 1, open-label, dose-escalation study of BIIB022 (anti-IGF-1R monoclonal antibody) in subjects with relapsed or refractory solid tumors. Invest New Drugs. 2014 Jun;32(3):518-25.

REF 45

The cyclolignan picropodophyllin attenuates intimal hyperplasia after rat carotid balloon injury by blocking insulin-like growth factor-1 receptor signaling. J Vasc Surg. 2007 Jul;46(1):108-15.

REF 46

Clinical pipeline report, company report or official report of Fusion Pharmaceuticals.

REF 47

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031207)

REF 48

Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growthfactor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin Cancer Res. 2009 Sep 1;15(17):5445-56.

REF 49

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

REF 50

Pfizer. Product Development Pipeline. March 31 2009.

REF 51

National Cancer Institute. NCI Drug Dictionary. 2009 (CdrID=456793)

REF 52

Discovery and evaluation of 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperidin-4-yl)-4-methyl-1H-benzo[d]imidazol-2-yl)py... J Med Chem. 2008 Oct 9;51(19):5897-900.

REF 53

Clinical pipeline report, company report or official report of Bristol-Myers Squibb.

REF 54

ATP non-competitive IGF-1 receptor kinase inhibitors as lead anti-neoplastic and anti-papilloma agents. Eur J Pharmacol. 2007 May 7;562(1-2):1-11.

REF 55

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 56

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 57

SAR of PXR transactivation in benzimidazole-based IGF-1R kinase inhibitors. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1744-8.

REF 58

Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.

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