Target General Infomation
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 [+] 2 Target-related Diseases +
1 Multiple structural anomalies syndrome [ICD-11: LD2F]
2 Pituitary gland disorder [ICD-11: 5A60-5A61]
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).
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
Drugs and Modes of Action
Approved Drug(s) [+] 2 Approved Drugs +
1 Mecasermin Drug Info Approved Growth failure [2], [3]
2 Somatomedin-1 Drug Info Approved Hormone deficiency [4]
Clinical Trial Drug(s) [+] 15 Clinical Trial Drugs +
1 OSI-906 Drug Info Phase 3 Solid tumour/cancer [5], [6]
2 Rinfabate Drug Info Phase 2/3 Solid tumour/cancer [7]
3 AMG 479 Drug Info Phase 2 Breast cancer [8]
4 AXL-1717 Drug Info Phase 2 Solid tumour/cancer [9], [10]
5 Cixutumumab Drug Info Phase 2 Non-small-cell lung cancer [11]
6 MM-141 Drug Info Phase 2 Solid tumour/cancer [12]
7 R1507 Drug Info Phase 2 Graves ophthalmopathy [13]
8 RV001 Drug Info Phase 2 Graves ophthalmopathy [14]
9 TT-100 Drug Info Phase 2 Non-small-cell lung cancer [15]
10 VPI-2690B Drug Info Phase 2 Diabetic nephropathy [16]
11 AEW-541 Drug Info Phase 1 Multiple myeloma [17]
12 BIIB 022 Drug Info Phase 1 Non-small-cell lung cancer [18]
13 Cyclolignan picropodophyllin Drug Info Phase 1 Colorectal cancer [19]
14 HF-0299 Drug Info Phase 1 Pain [20]
15 RG-7010 Drug Info Phase 1 Motor neurone disease [21]
Discontinued Drug(s) [+] 3 Discontinued Drugs +
1 AVE-1642 Drug Info Discontinued in Phase 2 Breast cancer [22]
2 KW-2450 Drug Info Discontinued in Phase 1/2 Breast cancer [23]
3 Figitumumab Drug Info Discontinued in Phase 1 Malignant adrenal gland cancer [24]
Preclinical Drug(s) [+] 2 Preclinical Drugs +
1 BMS-695735 Drug Info Preclinical Solid tumour/cancer [25]
2 EGFR/IGFR tandem adnectin Drug Info Preclinical Solid tumour/cancer [26]
Mode of Action [+] 3 Modes of Action +
Inhibitor [+] 19 Inhibitor drugs +
1 Mecasermin Drug Info [1], [27], [28], [29]
2 OSI-906 Drug Info [30]
3 AMG 479 Drug Info [32], [33]
4 AXL-1717 Drug Info [34]
5 R1507 Drug Info [37], [38]
6 TT-100 Drug Info [40]
7 AEW-541 Drug Info [41], [42], [43]
8 Cyclolignan picropodophyllin Drug Info [45]
9 Figitumumab Drug Info [49], [50]
10 BMS-695735 Drug Info [51]
11 EGFR/IGFR tandem adnectin Drug Info [52]
12 4-((1H-indazol-6-ylamino)methyl)benzene-1,2-diol Drug Info [53]
13 4-((naphthalen-2-ylamino)methyl)benzene-1,2-diol Drug Info [53]
14 Alpha-D-Mannose Drug Info [54]
15 AMP-PNP Drug Info [55]
16 BMS-536924 Drug Info [56]
17 Fucose Drug Info [54]
18 JB-1 Drug Info [57]
19 NVP-ADW742 Drug Info [57]
Modulator [+] 7 Modulator drugs +
1 Somatomedin-1 Drug Info [3]
2 Rinfabate Drug Info [31]
3 Cixutumumab Drug Info [35]
4 MM-141 Drug Info [36]
5 HF-0299 Drug Info [20]
6 RG-7010 Drug Info [46]
7 KW-2450 Drug Info [48]
Antagonist [+] 3 Antagonist drugs +
1 RV001 Drug Info [39], [16]
2 VPI-2690B Drug Info [16]
3 BIIB 022 Drug Info [44]
Target Regulators
Target-regulating microRNAs
Target-interacting Proteins
Target Profiles in Patients
Target Expression
 Profile (TEP)
Target Affiliated Biological Pathways
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
Target Validation
References
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 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 6 ClinicalTrials.gov (NCT00924989) A Study of OSI-906 in Patients With Locally Advanced or Metastatic Adrenocortical Carcinoma. U.S. National Institutes of Health.
REF 7 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 8 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 9 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: 7873).
REF 10 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 11 ClinicalTrials.gov (NCT01232452) A Study in Non-Small Cell Lung Cancer. U.S. National Institutes of Health.
REF 12 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 13 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 14 ClinicalTrials.gov (NCT01868997) Teprotumumab Treatment in Patients With Active Thyroid Eye Disease. U.S. National Institutes of Health.
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 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 21 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 22 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 23 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 24 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 25 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 26 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 27 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 28 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 29 Insulin-like growth factor I receptor gene structure. J Biol Chem. 1992 May 25;267(15):10759-63.
REF 30 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 31 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 32 Clinical pipeline report, company report or official report of Amgen (2009).
REF 33 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 34 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 35 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 36 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 37 Clinical pipeline report, company report or official report of Roche (2009).
REF 38 National Cancer Institute. Dictionary of Cancer Terms. 2009.
REF 39 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
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 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 47 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 48 Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
REF 49 Pfizer. Product Development Pipeline. March 31 2009.
REF 50 National Cancer Institute. NCI Drug Dictionary. 2009 (CdrID=456793)
REF 51 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 52 Clinical pipeline report, company report or official report of Bristol-Myers Squibb.
REF 53 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 54 How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 55 The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
REF 56 SAR of PXR transactivation in benzimidazole-based IGF-1R kinase inhibitors. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1744-8.
REF 57 Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.

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