Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Insulin receptor (INSR)
• Synonyms: IR; CD220 antigen; CD220
• Gene Name: INSR
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: INSR_HUMAN
• TTD ID: T85435
• EC Number: EC 2.7.10.1
• Sequence:
  MATGGRRGAAAAPLLVAVAALLLGAAGHLYPGEVCPGMDIRNNLTRLHELENCSVIEGHL
  QILLMFKTRPEDFRDLSFPKLIMITDYLLLFRVYGLESLKDLFPNLTVIRGSRLFFNYAL
  VIFEMVHLKELGLYNLMNITRGSVRIEKNNELCYLATIDWSRILDSVEDNYIVLNKDDNE
  ECGDICPGTAKGKTNCPATVINGQFVERCWTHSHCQKVCPTICKSHGCTAEGLCCHSECL
  GNCSQPDDPTKCVACRNFYLDGRCVETCPPPYYHFQDWRCVNFSFCQDLHHKCKNSRRQG
  CHQYVIHNNKCIPECPSGYTMNSSNLLCTPCLGPCPKVCHLLEGEKTIDSVTSAQELRGC
  TVINGSLIINIRGGNNLAAELEANLGLIEEISGYLKIRRSYALVSLSFFRKLRLIRGETL
  EIGNYSFYALDNQNLRQLWDWSKHNLTITQGKLFFHYNPKLCLSEIHKMEEVSGTKGRQE
  RNDIALKTNGDQASCENELLKFSYIRTSFDKILLRWEPYWPPDFRDLLGFMLFYKEAPYQ
  NVTEFDGQDACGSNSWTVVDIDPPLRSNDPKSQNHPGWLMRGLKPWTQYAIFVKTLVTFS
  DERRTYGAKSDIIYVQTDATNPSVPLDPISVSNSSSQIILKWKPPSDPNGNITHYLVFWE
  RQAEDSELFELDYCLKGLKLPSRTWSPPFESEDSQKHNQSEYEDSAGECCSCPKTDSQIL
  KELEESSFRKTFEDYLHNVVFVPRKTSSGTGAEDPRPSRKRRSLGDVGNVTVAVPTVAAF
  PNTSSTSVPTSPEEHRPFEKVVNKESLVISGLRHFTGYRIELQACNQDTPEERCSVAAYV
  SARTMPEAKADDIVGPVTHEIFENNVVHLMWQEPKEPNGLIVLYEVSYRRYGDEELHLCV
  SRKHFALERGCRLRGLSPGNYSVRIRATSLAGNGSWTEPTYFYVTDYLDVPSNIAKIIIG
  PLIFVFLFSVVIGSIYLFLRKRQPDGPLGPLYASSNPEYLSASDVFPCSVYVPDEWEVSR
  EKITLLRELGQGSFGMVYEGNARDIIKGEAETRVAVKTVNESASLRERIEFLNEASVMKG
  FTCHHVVRLLGVVSKGQPTLVVMELMAHGDLKSYLRSLRPEAENNPGRPPPTLQEMIQMA
  AEIADGMAYLNAKKFVHRDLAARNCMVAHDFTVKIGDFGMTRDIYETDYYRKGGKGLLPV
  RWMAPESLKDGVFTTSSDMWSFGVVLWEITSLAEQPYQGLSNEQVLKFVMDGGYLDQPDN
  CPERVTDLMRMCWQFNPKMRPTFLEIVNLLKDDLHPSFPEVSFFHSEENKAPESEELEME
  FEDMENVPLDRSSHCQREEAGGRDGGSSLGFKRSYEEHIPYTHMNGGKKNGRILTLPRSN
  PS
• Function: Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosine residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. Receptor tyrosine kinase which mediates the pleiotropic actions of insulin.
• KEGG Pathway:
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  cGMP-PKG signaling pathway (hsa04022)
  HIF-1 signaling pathway (hsa04066)
  FoxO signaling pathway (hsa04068)
  PI3K-Akt signaling pathway (hsa04151)
  AMPK signaling pathway (hsa04152)
  Adherens junction (hsa04520)
  Insulin signaling pathway (hsa04910)
  Ovarian steroidogenesis (hsa04913)
  Type II diabetes mellitus (hsa04930)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Aldosterone-regulated sodium reabsorption (hsa04960)
• Reactome Pathway:
  Signal attenuation (R-HSA-74749)
  Insulin receptor signalling cascade (R-HSA-74751)
  Insulin receptor recycling (R-HSA-77387)
  IRS activation (R-HSA-74713)

Molecular Interaction Atlas (MIA) of This DTT

9 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Human neutral insulin	DMA5OBU	Diabetic complication	5A2Y	Approved	[2]
Insulin Lyspro recombinant	DM5XHVR	Diabetic complication	5A2Y	Approved	[2]
Insulin recombinant	DMYVP5G	Diabetic complication	5A2Y	Approved	[2]
Insulin, porcine	DMO95XI	Diabetic complication	5A2Y	Approved	[3]
Insulin-glulisine	DMQI0FU	Diabetic complication	5A2Y	Approved	[4]
Insulin-lispro	DM4O90W	Diabetic complication	5A2Y	Approved	[5]
Meglitinides	DM1OFHN	Type-2 diabetes	5A11	Approved	[1]
Metformin arginine-hemisuccinimide	DMTPAM3	Type-2 diabetes	5A11	Approved	[6]
Ryzodeq	DMOFP18	Type-2 diabetes	5A11	Approved	[7]

19 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
NN5401	DM0QV27	Diabetic complication	5A2Y	Phase 3	[7]
Metformin glycinate	DMFE0P1	Type-2 diabetes	5A11	Phase 2/3	[8]
DM-71	DMMSIG7	Type-2 diabetes	5A11	Phase 2	[7]
DM-99	DM1HG3U	Alzheimer disease	8A20	Phase 2	[7]
EGS-21	DMN1SWB	Crohn disease	DD70	Phase 2	[9]
Mitoglitazone	DMIRPSA	Alzheimer disease	8A20	Phase 2	[10]
MSDC-0602	DMGUI51	Type-2 diabetes	5A11	Phase 2	[11]
NP-01	DMP1W9Z	Type-2 diabetes	5A11	Phase 2	[7]
RZ358	DMN32UV	Congenital hyperinsulinism	5A4Y	Phase 2	[12]
S-707106	DM3GRKY	Type-2 diabetes	5A11	Phase 2	[7]
TAK-379	DMEYKRN	Type-2 diabetes	5A11	Phase 2	[7]
Tesofensine	DM1KGS7	Pain	MG30-MG3Z	Phase 2	[13]
VVP-808	DM6BKG2	Type-2 diabetes	5A11	Phase 2	[7]
AEW-541	DMQF982	Multiple myeloma	2A83	Phase 1	[14]
AGT-182	DML79KE	Hunter syndrome	5C56.31	Phase 1	[7]
Insulin oral sublingual	DMMR7CH	Type-1 diabetes	5A10	Phase 1	[7]
Insulin transdermal	DM93QP2	Type-1/2 diabetes	5A10-5A11	Phase 1	[15]
ISF-402	DMKO7EA	Type-2 diabetes	5A11	Phase 1	[16]
NN-1218	DMDGCHR	Diabetic complication	5A2Y	Phase 1	[17]

6 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AKP-020	DM6IPWN	Type-2 diabetes	5A11	Discontinued in Phase 2	[18]
DM-83	DMIP3EC	Type-2 diabetes	5A11	Discontinued in Phase 2	[7]
EML-336	DMML2PX	Type-2 diabetes	5A11	Discontinued in Phase 2	[7]
KW-2450	DM7QGSX	Breast cancer	2C60-2C65	Discontinued in Phase 1/2	[19]
CLX-0900	DMYPRS9	Hyperlipidaemia	5C80	Terminated	[20]
TER-16998	DMQIYZR	Diabetic complication	5A2Y	Terminated	[7]

14 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	[21]
4-((naphthalen-2-ylamino)methyl)benzene-1,2-diol	DM52Y3Q	Discovery agent	N.A.	Investigative	[21]
AD10-1025	DMYLA29	Hypercholesterolaemia	5C80.0	Investigative	[7]
DC-9703	DM62IBX	Non-insulin dependent diabetes	5A11	Investigative	[7]
FPT-038	DM0T2LQ	Non-insulin dependent diabetes	5A11	Investigative	[7]
GSK-1838705A	DM4HLK3	Discovery agent	N.A.	Investigative	[22]
L-betagamma-meATP	DMTNQCE	Discovery agent	N.A.	Investigative	[23]
NVP-TAE684	DMFZXI2	Lymphoma	2A80-2A86	Investigative	[24]
PMID24900237C15	DM6TFPY	Discovery agent	N.A.	Investigative	[25]
Quick-acting insulin	DM9YWG8	Diabetic complication	5A2Y	Investigative	[7]
RHIIP	DMWP09B	Diabetic complication	5A2Y	Investigative	[26]
VVP-100X	DMEZAND	Non-insulin dependent diabetes	5A11	Investigative	[7]
XMetD	DMHWTCY	Hypoglycemia	5A41	Investigative	[7]
XMetS	DM6JKL7	Non-insulin dependent diabetes	5A11	Investigative	[7]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	1.03E-05	0.26	0.66
Breast cancer	2C82	Breast tissue	4.71E-25	-0.38	-0.82
Type 2 diabetes	5A11	Liver tissue	7.67E-01	0.11	0.26
Familial hypercholesterolemia	5A11	Whole blood	4.08E-08	0.69	1.94

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