Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Insulin (INS)
• Synonyms: Insulin
• Gene Name: INS
• DTT Type: Successful target; [1]
• Related Disease:
  Acute diabete complication [ICD-11: 5A2Y]
  Kidney malfunction [ICD-11: MG02]
  Type-1/2 diabete [ICD-11: 5A10-5A11]
• UniProt ID: INS_HUMAN
• TTD ID: T82841
• Sequence:
  MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAED
  LQVGQVELGGGPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN
• Function: Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
• KEGG Pathway:
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  cGMP-PKG signaling pathway (hsa04022)
  HIF-1 signaling pathway (hsa04066)
  FoxO signaling pathway (hsa04068)
  Oocyte meiosis (hsa04114)
  Regulation of autophagy (hsa04140)
  mTOR signaling pathway (hsa04150)
  PI3K-Akt signaling pathway (hsa04151)
  AMPK signaling pathway (hsa04152)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin signaling pathway (hsa04910)
  Insulin secretion (hsa04911)
  Ovarian steroidogenesis (hsa04913)
  Progesterone-mediated oocyte maturation (hsa04914)
  Prolactin signaling pathway (hsa04917)
  Type II diabetes mellitus (hsa04930)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Type I diabetes mellitus (hsa04940)
  Maturity onset diabetes of the young (hsa04950)
  Aldosterone-regulated sodium reabsorption (hsa04960)
  Prostate cancer (hsa05215)
• Reactome Pathway:
  Insulin processing (R-HSA-264876)
  Regulation of insulin secretion (R-HSA-422356)
  IRS activation (R-HSA-74713)
  Signal attenuation (R-HSA-74749)
  Insulin receptor signalling cascade (R-HSA-74751)
  Insulin receptor recycling (R-HSA-77387)
  Regulation of gene expression in beta cells (R-HSA-210745)
• BioCyc Pathway: MetaCyc:MON-16190

Molecular Interaction Atlas (MIA) of This DTT

9 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Insulin degludec	DMPL395	Type-1/2 diabetes	5A10-5A11	Approved	[2]
Insulin determir	DM79NZ5	Diabetic complication	5A2Y	Approved	[1]
Insulin Susp Isophane Recombinant Human	DMW8KI7	Diabetic complication	5A2Y	Approved	[3]
Insulin Susp Protamine Zinc Beef/Pork	DM0NATE	Diabetic complication	5A2Y	Approved	[3]
Insulin Zinc Susp Recombinant Human	DM6MO9X	Diabetic complication	5A2Y	Approved	[3]
Insulin-aspart	DMX7V28	Diabetic complication	5A2Y	Approved	[3]
Insulin-detemir	DMOA4VW	Type-1/2 diabetes	5A10-5A11	Approved	[3]
Insulin-glargine	DMR4HIW	Diabetic complication	5A2Y	Approved	[3]
Inulin	DM1Y2JH	Measure kidney function	MG02	Approved	[3]

14 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LY2605541	DM1BXMY	Type-1/2 diabetes	5A10-5A11	Phase 3	[4]
LY2963016	DMEZ0H5	Type-1/2 diabetes	5A10-5A11	Phase 3	[5]
PC-DAC:Insulin	DMJBHO0	Type-1 diabetes	5A10	Phase 3	[6], [7]
SAR342434	DMR0EWV	Diabetic complication	5A2Y	Phase 3	[8]
U300	DMN72OM	Type-2 diabetes	5A11	Phase 3	[9]
MER-3001	DMIVR9K	Type-1 diabetes	5A10	Phase 2	[10]
NNC-0123-0000-0338	DMDTNOS	Diabetic complication	5A2Y	Phase 2	[11]
SAR-161271	DMPXOGD	Type-1 diabetes	5A10	Phase 1/2	[12]
Adjustable basal insulin	DMQVEZB	Diabetic complication	5A2Y	Phase 1	[13]
IBC-VS01	DMRE6UT	Type-1 diabetes	5A10	Phase 1	[14]
NP-500	DMHARE7	Metabolic syndrome x	5C50-5D2Z	Phase 1	[15]
OI287GT	DMH0D5M	Type-1/2 diabetes	5A10-5A11	Phase 1	[16]
OI362GT	DMERDMV	Type-1/2 diabetes	5A10-5A11	Phase 1	[17]
SBS-1000	DMXU2GS	Diabetic complication	5A2Y	Phase 1	[18]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
NBI-6024	DMTRMBL	Type-1 diabetes	5A10	Discontinued in Phase 2	[19], [20]
S-15261	DMLCYX8	Diabetic complication	5A2Y	Discontinued in Phase 2	[21]
FT-105	DMDW64X	Diabetic complication	5A2Y	Discontinued in Phase 1	[22]
Oral insulin	DMW68CE	Type-1 diabetes	5A10	Terminated	[23]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Insulin molecules, Novo	DMFU92Z	Discovery agent	N.A.	Investigative	[24]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Type 2 diabetes	5A11	Liver tissue	6.70E-01	-0.12	-0.46

References

• [1] 2005 approvals: Safety first. Nature Reviews Drug Discovery 5, 92-93 (February 2006).
• [2] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [4] LY2605541--a preferential hepato-specific insulin analogue. Diabetes. 2014 Feb;63(2):390-2.
• [5] Efficacy and safety of LY2963016 insulin glargine compared with insulin glargine (Lantus ) in patients with type 1 diabetes in a randomized controlled trial: the ELEMENT 1 study. Diabetes Obes Metab.2015 Aug;17(8):726-33.
• [6] Development and Testing of Solid Dose Formulations Containing Polysialic Acid Insulin Conjugate: Next Generation of Long-Acting Insulin. J Diabetes Sci Technol. 2010 May; 4(3): 532-539.
• [7] Inhaled Insulin: Promises and Concerns. J Diabetes Sci Technol. 2008 March; 2(2): 311-315.
• [8] Biosimilar insulins: a European perspective. Diabetes Obes Metab. 2015 May; 17(5): 445-451.
• [9] U300, a novel long-acting insulin formulation. Expert Opin Biol Ther. 2014 Dec;14(12):1849-60.
• [10] Clinical pipeline report, company report or official report of Mercia Pharma Inc.
• [11] ClinicalTrials.gov (NCT01334034) Safety of NNC 0123-0000-0338 in Healthy Subjects. U.S. National Institutes of Health.
• [12] Clinical pipeline report, company report or official report of sanofi-aventis.
• [13] The future of basal insulin supplementation. Diabetes Technol Ther. 2011 Jun;13 Suppl 1:S103-8.
• [14] Prevention of Type 1 Diabetes Mellitus using a Novel Vaccine. Ther Adv Endocrinol Metab. 2011 February; 2(1): 9-16.
• [15] Napo Receives Commitments for a Private Placement of Common Shares and Enters into Binding Letter of Intent for Intellectual Property License. Napo. JANUARY 08, 2007
• [16] Company report (Novonordisk)
• [17] Novo Nordisk increased operating profit in local currencies by 15% in the first quarter of 2014
• [18] Synergistic antihyperglycemic effects between plant-derived oleanolic acid and insulin in streptozotocin-induced diabetic rats. Ren Fail. 2010;32(7):832-9.
• [19] No effect of the altered peptide ligand NBI-6024 on beta-cell residual function and insulin needs in new-onset type 1 diabetes.Diabetes Care.2009 Nov;32(11):2036-40.
• [20] Immunological characterization and therapeutic activity of an altered-peptide ligand, NBI-6024, based on the immunodominant type 1 diabetes autoantigen insulin B-chain (9-23) peptide. Diabetes. 2002 Jul;51(7):2126-34.
• [21] Beneficial insulin-sensitizing and vascular effects of S15261 in the insulin-resistant JCR:LA-cp rat. J Pharmacol Exp Ther. 2000 Nov;295(2):753-60.
• [22] Degludec insulin: A novel basal insulin. Indian J Endocrinol Metab. 2011 July; 15(Suppl1): S12-S16.
• [23] ClinicalTrials.gov (NCT01120912) Safety and Efficacy of Single Administration of Oshadi Oral Insulin in Type I Diabetes Patients. U.S. National Institutes of Health.
• [24] Long-term comparison of human insulin analogue B10Asp and soluble human insulin in IDDM patients on a basal/bolus insulin regimen. Diabetologia. 1995 May;38(5):592-8.