Target Information
Target General Information | Top | |||||
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Target ID |
T48069
(Former ID: TTDS00269)
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Target Name |
Insulin-like growth factor I receptor (IGF1R)
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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
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Gene Name |
IGF1R
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Multiple structural anomalies syndrome [ICD-11: LD2F] | |||||
2 | Pituitary gland disorder [ICD-11: 5A60-5A61] | |||||
3 | 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
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UniProt ID | ||||||
EC Number |
EC 2.7.10.1
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Sequence |
MKSGSGGGSPTSLWGLLFLSAALSLWPTSGEICGPGIDIRNDYQQLKRLENCTVIEGYLH
ILLISKAEDYRSYRFPKLTVITEYLLLFRVAGLESLGDLFPNLTVIRGWKLFYNYALVIF EMTNLKDIGLYNLRNITRGAIRIEKNADLCYLSTVDWSLILDAVSNNYIVGNKPPKECGD LCPGTMEEKPMCEKTTINNEYNYRCWTTNRCQKMCPSTCGKRACTENNECCHPECLGSCS APDNDTACVACRHYYYAGVCVPACPPNTYRFEGWRCVDRDFCANILSAESSDSEGFVIHD GECMQECPSGFIRNGSQSMYCIPCEGPCPKVCEEEKKTKTIDSVTSAQMLQGCTIFKGNL LINIRRGNNIASELENFMGLIEVVTGYVKIRHSHALVSLSFLKNLRLILGEEQLEGNYSF YVLDNQNLQQLWDWDHRNLTIKAGKMYFAFNPKLCVSEIYRMEEVTGTKGRQSKGDINTR NNGERASCESDVLHFTSTTTSKNRIIITWHRYRPPDYRDLISFTVYYKEAPFKNVTEYDG QDACGSNSWNMVDVDLPPNKDVEPGILLHGLKPWTQYAVYVKAVTLTMVENDHIRGAKSE ILYIRTNASVPSIPLDVLSASNSSSQLIVKWNPPSLPNGNLSYYIVRWQRQPQDGYLYRH NYCSKDKIPIRKYADGTIDIEEVTENPKTEVCGGEKGPCCACPKTEAEKQAEKEEAEYRK VFENFLHNSIFVPRPERKRRDVMQVANTTMSSRSRNTTAADTYNITDPEELETEYPFFES RVDNKERTVISNLRPFTLYRIDIHSCNHEAEKLGCSASNFVFARTMPAEGADDIPGPVTW EPRPENSIFLKWPEPENPNGLILMYEIKYGSQVEDQRECVSRQEYRKYGGAKLNRLNPGN YTARIQATSLSGNGSWTDPVFFYVQAKTGYENFIHLIIALPVAVLLIVGGLVIMLYVFHR KRNNSRLGNGVLYASVNPEYFSAADVYVPDEWEVAREKITMSRELGQGSFGMVYEGVAKG VVKDEPETRVAIKTVNEAASMRERIEFLNEASVMKEFNCHHVVRLLGVVSQGQPTLVIME LMTRGDLKSYLRSLRPEMENNPVLAPPSLSKMIQMAGEIADGMAYLNANKFVHRDLAARN CMVAEDFTVKIGDFGMTRDIYETDYYRKGGKGLLPVRWMSPESLKDGVFTTYSDVWSFGV VLWEIATLAEQPYQGLSNEQVLRFVMEGGLLDKPDNCPDMLFELMRMCWQYNPKMRPSFL EIISSIKEEMEPGFREVSFYYSEENKLPEPEELDLEPENMESVPLDPSASSSSLPLPDRH SGHKAENGPGPGVLVLRASFDERQPYAHMNGGRKNERALPLPQSSTC Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T42XY2 |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 3 Approved Drugs | + | ||||
1 | Mecasermin | Drug Info | Approved | Growth failure | [2], [3] | |
2 | Somatomedin-1 | Drug Info | Approved | Hormone deficiency | [4] | |
3 | Teprotumumab | Drug Info | Approved | Graves disease | [5] | |
Clinical Trial Drug(s) | [+] 15 Clinical Trial Drugs | + | ||||
1 | OSI-906 | Drug Info | Phase 3 | Solid tumour/cancer | [6], [7] | |
2 | Rinfabate | Drug Info | Phase 2/3 | Solid tumour/cancer | [8] | |
3 | AMG 479 | Drug Info | Phase 2 | Breast cancer | [9] | |
4 | AXL-1717 | Drug Info | Phase 2 | Solid tumour/cancer | [10], [11] | |
5 | Cixutumumab | Drug Info | Phase 2 | Non-small-cell lung cancer | [12] | |
6 | MM-141 | Drug Info | Phase 2 | Solid tumour/cancer | [13] | |
7 | R1507 | Drug Info | Phase 2 | Graves ophthalmopathy | [14] | |
8 | TT-100 | Drug Info | Phase 2 | Non-small-cell lung cancer | [15] | |
9 | VPI-2690B | Drug Info | Phase 2 | Diabetic nephropathy | [16] | |
10 | AEW-541 | Drug Info | Phase 1 | Multiple myeloma | [17] | |
11 | BIIB 022 | Drug Info | Phase 1 | Non-small-cell lung cancer | [18] | |
12 | Cyclolignan picropodophyllin | Drug Info | Phase 1 | Colorectal cancer | [19] | |
13 | FPI-1434 | Drug Info | Phase 1 | Solid tumour/cancer | [20] | |
14 | HF-0299 | Drug Info | Phase 1 | Pain | [21] | |
15 | RG-7010 | Drug Info | Phase 1 | Motor neurone disease | [22] | |
Discontinued Drug(s) | [+] 3 Discontinued Drugs | + | ||||
1 | AVE-1642 | Drug Info | Discontinued in Phase 2 | Breast cancer | [23] | |
2 | KW-2450 | Drug Info | Discontinued in Phase 1/2 | Breast cancer | [24] | |
3 | Figitumumab | Drug Info | Discontinued in Phase 1 | Malignant adrenal gland cancer | [25] | |
Preclinical Drug(s) | [+] 2 Preclinical Drugs | + | ||||
1 | BMS-695735 | Drug Info | Preclinical | Solid tumour/cancer | [26] | |
2 | EGFR/IGFR tandem adnectin | Drug Info | Preclinical | Solid tumour/cancer | [27] | |
Mode of Action | [+] 3 Modes of Action | + | ||||
Inhibitor | [+] 19 Inhibitor drugs | + | ||||
1 | Mecasermin | Drug Info | [1], [28], [29], [30] | |||
2 | OSI-906 | Drug Info | [31] | |||
3 | AMG 479 | Drug Info | [33], [34] | |||
4 | AXL-1717 | Drug Info | [35] | |||
5 | R1507 | Drug Info | [38], [39] | |||
6 | TT-100 | Drug Info | [40] | |||
7 | AEW-541 | Drug Info | [41], [42], [43] | |||
8 | Cyclolignan picropodophyllin | Drug Info | [45] | |||
9 | Figitumumab | Drug Info | [50], [51] | |||
10 | BMS-695735 | Drug Info | [52] | |||
11 | EGFR/IGFR tandem adnectin | Drug Info | [53] | |||
12 | 4-((1H-indazol-6-ylamino)methyl)benzene-1,2-diol | Drug Info | [54] | |||
13 | 4-((naphthalen-2-ylamino)methyl)benzene-1,2-diol | Drug Info | [54] | |||
14 | Alpha-D-Mannose | Drug Info | [55] | |||
15 | AMP-PNP | Drug Info | [56] | |||
16 | BMS-536924 | Drug Info | [57] | |||
17 | Fucose | Drug Info | [55] | |||
18 | JB-1 | Drug Info | [58] | |||
19 | NVP-ADW742 | Drug Info | [58] | |||
Modulator | [+] 7 Modulator drugs | + | ||||
1 | Somatomedin-1 | Drug Info | [3] | |||
2 | Rinfabate | Drug Info | [32] | |||
3 | Cixutumumab | Drug Info | [36] | |||
4 | MM-141 | Drug Info | [37] | |||
5 | HF-0299 | Drug Info | [21] | |||
6 | RG-7010 | Drug Info | [47] | |||
7 | KW-2450 | Drug Info | [49] | |||
Antagonist | [+] 3 Antagonist drugs | + | ||||
1 | Teprotumumab | Drug Info | [5] | |||
2 | VPI-2690B | Drug Info | [16] | |||
3 | BIIB 022 | Drug Info | [44] |
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"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 | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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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 | 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 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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