Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTHRID2)

• DTT 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
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: IGF1R_HUMAN
• TTD ID: T48069
• 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
• 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).
• KEGG Pathway:
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  HIF-1 signaling pathway (hsa04066)
  FoxO signaling pathway (hsa04068)
  Oocyte meiosis (hsa04114)
  Endocytosis (hsa04144)
  PI3K-Akt signaling pathway (hsa04151)
  AMPK signaling pathway (hsa04152)
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Long-term depression (hsa04730)
  Ovarian steroidogenesis (hsa04913)
  Progesterone-mediated oocyte maturation (hsa04914)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Proteoglycans in cancer (hsa05205)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Melanoma (hsa05218)
• Reactome Pathway:
  SHC-related events triggered by IGF1R (R-HSA-2428933)
  IRS-related events triggered by IGF1R (R-HSA-2428928)

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Mecasermin	DM1O3BY	Growth failure	LD2F.1Y	Approved	[1]
Somatomedin-1	DMZ9FAO	Hormone deficiency	5A61.1	Approved	[2]
Teprotumumab	DM4L59B	Graves disease	5A02.0	Approved	[3]

16 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
OSI-906	DMHKZLF	Solid tumour/cancer	2A00-2F9Z	Phase 3	[4]
Rinfabate	DML9FD4	Solid tumour/cancer	2A00-2F9Z	Phase 2/3	[5]
AMG 479	DM0DRAZ	Breast cancer	2C60-2C65	Phase 2	[6]
AXL-1717	DMTQ1Y3	Solid tumour/cancer	2A00-2F9Z	Phase 2	[7]
Cixutumumab	DMNRYPF	Liver cancer	2C12	Phase 2	[8]
MM-141	DM2RJ4D	Pancreatic cancer	2C10	Phase 2	[9]
R1507	DMIUS5X	Graves ophthalmopathy	9C82.3	Phase 2	[10]
TT-100	DMZE6Y9	Non-small-cell lung cancer	2C25.Y	Phase 2	[11]
VPI-2690B	DMUQZT4	Diabetic nephropathy	GB61.Z	Phase 2	[12]
AEW-541	DMQF982	Multiple myeloma	2A83	Phase 1	[13]
BIIB 022	DMZ1V0E	Hepatocellular carcinoma	2C12.02	Phase 1	[14]
Cyclolignan picropodophyllin	DMI6EUB	Colorectal cancer	2B91.Z	Phase 1	[15]
FPI-1434	DMI9A1Z	Solid tumour/cancer	2A00-2F9Z	Phase 1	[16]
HF-0299	DMDZQ23	Pain	MG30-MG3Z	Phase 1	[17]
RG-7010	DMMWS3O	Motor neurone disease	8B60	Phase 1	[18]
SAR446159	DMWAO33	Parkinson disease	8A00.0	Phase 1	[19]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AVE-1642	DMUQ6IL	Breast cancer	2C60-2C65	Discontinued in Phase 2	[20]
KW-2450	DM7QGSX	Breast cancer	2C60-2C65	Discontinued in Phase 1/2	[21]
Figitumumab	DMC3DVB	Malignant adrenal gland cancer	2D11	Discontinued in Phase 1	[22]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-695735	DMQG39T	Solid tumour/cancer	2A00-2F9Z	Preclinical	[23]
EGFR/IGFR tandem adnectin	DMZ3YP6	Solid tumour/cancer	2A00-2F9Z	Preclinical	[24]

8 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-((1H-indazol-6-ylamino)methyl)benzene-1,2-diol	DMLV59R	Discovery agent	N.A.	Investigative	[25]
4-((naphthalen-2-ylamino)methyl)benzene-1,2-diol	DM52Y3Q	Discovery agent	N.A.	Investigative	[25]
Alpha-D-Mannose	DMF5DLW	Discovery agent	N.A.	Investigative	[26]
AMP-PNP	DMTOK1D	Discovery agent	N.A.	Investigative	[27]
BMS-536924	DMXJB4N	Discovery agent	N.A.	Investigative	[28]
Fucose	DMAHMSV	N. A.	N. A.	Investigative	[26]
JB-1	DM38L1B	Multiple myeloma	2A83	Investigative	[29]
NVP-ADW742	DMXL3CD	Multiple myeloma	2A83	Investigative	[29]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rectal cancer	2C82	Rectal colon tissue	1.64E-01	0.25	0.64
Multiple myeloma	2C82	Bone marrow	5.61E-01	-0.01	-0.04
Adrenocortical carcinoma	2C82	Kidney	8.97E-02	-0.33	-0.62
Lung cancer	2C82	Lung tissue	6.95E-04	0.11	0.19
Breast cancer	2C82	Breast tissue	9.93E-08	0.54	0.57

References

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• [24] Clinical pipeline report, company report or official report of Bristol-Myers Squibb.
• [25] 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.
• [26] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
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• [29] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.