Target Information

Target General Information

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Target ID

T82841 (Former ID: TTDNC00576)

Target Name

Insulin (INS)

Synonyms

Insulin

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Gene Name

INS

Target Type

Successful target

[1]

Disease

[+] 3 Target-related Diseases

Acute diabete complication [ICD-11: 5A2Y]

Kidney malfunction [ICD-11: MG02]

Type-1/2 diabete [ICD-11: 5A10-5A11]

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.

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UniProt ID

INS_HUMAN

Sequence

MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAED
LQVGQVELGGGPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN

Click to Show/Hide

3D Structure

Click to Show 3D Structure of This Target

PDB

ADReCS ID

BADD_A02189 ; BADD_A02399 ; BADD_A02651

HIT2.0 ID

T89L4V

Drugs and Modes of Action

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Approved Drug(s)

[+] 9 Approved Drugs

Insulin degludec

Drug Info

Approved

Type-1/2 diabetes

[2]

Insulin determir

Drug Info

Approved

Diabetic complication

[3]

Insulin Susp Isophane Recombinant Human

Drug Info

Approved

Diabetic complication

[3]

Insulin Susp Protamine Zinc Beef/Pork

Drug Info

Approved

Diabetic complication

[3]

Insulin Zinc Susp Recombinant Human

Drug Info

Approved

Diabetic complication

[3]

Insulin-aspart

Drug Info

Approved

Diabetic complication

[4]

Insulin-detemir

Drug Info

Approved

Type-1/2 diabetes

[1], [4]

Insulin-glargine

Drug Info

Approved

Diabetic complication

[4], [5]

Inulin

Drug Info

Approved

Measure kidney function

[4]

Clinical Trial Drug(s)

[+] 14 Clinical Trial Drugs

LY2605541

Drug Info

Phase 3

Type-1/2 diabetes

[6]

LY2963016

Drug Info

Phase 3

Type-1/2 diabetes

[7]

PC-DAC:Insulin

Drug Info

Phase 3

Type-1 diabetes

[8]

SAR342434

Drug Info

Phase 3

Diabetic complication

[9]

U300

Drug Info

Phase 3

Type-2 diabetes

[10]

MER-3001

Drug Info

Phase 2

Type-1 diabetes

[11]

NNC-0123-0000-0338

Drug Info

Phase 2

Diabetic complication

[12]

SAR-161271

Drug Info

Phase 1/2

Type-1 diabetes

[13]

Adjustable basal insulin

Drug Info

Phase 1

Diabetic complication

[14]

IBC-VS01

Drug Info

Phase 1

Type-1 diabetes

[15]

NP-500

Drug Info

Phase 1

Type-2 diabetes

[16]

OI287GT

Drug Info

Phase 1

Type-1/2 diabetes

[17]

OI362GT

Drug Info

Phase 1

Type-1/2 diabetes

[18]

SBS-1000

Drug Info

Phase 1

Diabetic complication

[19]

Discontinued Drug(s)

[+] 4 Discontinued Drugs

NBI-6024

Drug Info

Discontinued in Phase 2

Type-1 diabetes

[20]

S-15261

Drug Info

Discontinued in Phase 2

Diabetic complication

[21]

FT-105

Drug Info

Discontinued in Phase 1

Diabetic complication

[22]

Oral insulin

Drug Info

Terminated

Type-1 diabetes

[23]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 27 Modulator drugs

Insulin degludec

Drug Info

[2]

Insulin determir

Drug Info

[1]

Insulin Susp Isophane Recombinant Human

Drug Info

[24]

Insulin Susp Protamine Zinc Beef/Pork

Drug Info

[24]

Insulin Zinc Susp Recombinant Human

Drug Info

[24]

Insulin-aspart

Drug Info

[24]

Insulin-detemir

Drug Info

[24]

Insulin-glargine

Drug Info

[24]

Inulin

Drug Info

[24]

LY2605541

Drug Info

[25]

PC-DAC:Insulin

Drug Info

[27], [28]

SAR342434

Drug Info

[29]

U300

Drug Info

[30]

MER-3001

Drug Info

[31]

NNC-0123-0000-0338

Drug Info

[32]

SAR-161271

Drug Info

[33]

Adjustable basal insulin

Drug Info

[34]

IBC-VS01

Drug Info

[35]

NP-500

Drug Info

[36]

OI287GT

Drug Info

[37]

OI362GT

Drug Info

[38]

SBS-1000

Drug Info

[39]

NBI-6024

Drug Info

[40], [41]

S-15261

Drug Info

[42]

FT-105

Drug Info

[43]

Oral insulin

Drug Info

[44]

Insulin molecules, Novo

Drug Info

[45]

Agonist

[+] 1 Agonist drugs

LY2963016

Drug Info

[26]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Urea

Ligand Info

Structure Description

Structure of human insulin cocrystallized with ARG-12 peptide in presence of urea

PDB:2OMH

Method

X-ray diffraction

Resolution

1.36 Å

Mutation

[46]

PDB Sequence

GIVEQCCTSI

¹⁰

CSLYQLENYC

²⁰

Residue

Distance (Å)

GLN5

2.873

CYS6

4.754

SER9

3.432

Residue

Distance (Å)

ILE10

3.319

CYS11

3.425

GLN15

3.598

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: Arginine

Ligand Info

Structure Description

Human insulin in complex with serotonin and arginine

PDB:5MT9

Method

X-ray diffraction

Resolution

1.88 Å

Mutation

[47]

PDB Sequence

HLCGSHLVEA

¹⁴

LYLVCGERGF

²⁴

FYTPK

Residue

Distance (Å)

HIS5

2.715

LEU6

3.263

CYS7

2.904

HIS10

2.645

Residue

Distance (Å)

LEU11

4.562

GLU13

2.386

ALA14

3.963

Click to View More Binding Site Information of This Target and Ligand Pair

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
MAPK signaling pathway	hsa04010	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Ras signaling pathway	hsa04014	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Rap1 signaling pathway	hsa04015	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
cGMP-PKG signaling pathway	hsa04022	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
HIF-1 signaling pathway	hsa04066	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
FoxO signaling pathway	hsa04068	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Phospholipase D signaling pathway	hsa04072	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Oocyte meiosis	hsa04114	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Autophagy - animal	hsa04140	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
mTOR signaling pathway	hsa04150	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
PI3K-Akt signaling pathway	hsa04151	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
AMPK signaling pathway	hsa04152	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Longevity regulating pathway	hsa04211	Affiliated Target
Class: Organismal Systems => Aging	Pathway Hierarchy
Longevity regulating pathway - multiple species	hsa04213	Affiliated Target
Class: Organismal Systems => Aging	Pathway Hierarchy
Regulation of actin cytoskeleton	hsa04810	Affiliated Target
Class: Cellular Processes => Cell motility	Pathway Hierarchy
Insulin signaling pathway	hsa04910	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Insulin secretion	hsa04911	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Ovarian steroidogenesis	hsa04913	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Progesterone-mediated oocyte maturation	hsa04914	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Prolactin signaling pathway	hsa04917	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Regulation of lipolysis in adipocytes	hsa04923	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Aldosterone-regulated sodium reabsorption	hsa04960	Affiliated Target
Class: Organismal Systems => Excretory system	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	44	Degree centrality	4.73E-03	Betweenness centrality	9.78E-03
Closeness centrality	2.56E-01	Radiality	1.44E+01	Clustering coefficient	1.25E-01
Neighborhood connectivity	3.50E+01	Topological coefficient	4.61E-02	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Target Regulators

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Target-regulating Transcription Factors

Target-regulating Transcription Factors Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 22 KEGG Pathways	+
1	Ras signaling pathway
2	Rap1 signaling pathway
3	cGMP-PKG signaling pathway
4	HIF-1 signaling pathway
5	FoxO signaling pathway
6	Oocyte meiosis
7	Regulation of autophagy
8	mTOR signaling pathway
9	PI3K-Akt signaling pathway
10	AMPK signaling pathway
11	Regulation of actin cytoskeleton
12	Insulin signaling pathway
13	Insulin secretion
14	Ovarian steroidogenesis
15	Progesterone-mediated oocyte maturation
16	Prolactin signaling pathway
17	Type II diabetes mellitus
18	Non-alcoholic fatty liver disease (NAFLD)
19	Type I diabetes mellitus
20	Maturity onset diabetes of the young
21	Aldosterone-regulated sodium reabsorption
22	Prostate cancer
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
Pathwhiz Pathway	[+] 3 Pathwhiz Pathways	+
1	Insulin Signalling
2	Pancreas Function
3	Leucine Stimulation on Insulin Signaling
PID Pathway	[+] 8 PID Pathways	+
1	Insulin Pathway
2	Signaling events mediated by PTP1B
3	Arf6 trafficking events
4	Signaling events mediated by TCPTP
5	FOXA2 and FOXA3 transcription factor networks
6	ATF-2 transcription factor network
7	Insulin-mediated glucose transport
8	FOXA1 transcription factor network
Reactome	[+] 7 Reactome Pathways	+
1	Regulation of gene expression in beta cells
2	Insulin processing
3	Regulation of insulin secretion
4	IRS activation
5	Signal attenuation
6	Insulin receptor signalling cascade
7	Insulin receptor recycling
WikiPathways	[+] 16 WikiPathways	+
1	Senescence and Autophagy in Cancer
2	Differentiation Pathway
3	Insulin Processing
4	Nanoparticle triggered autophagic cell death
5	Cardiac Progenitor Differentiation
6	Adipogenesis
7	AGE/RAGE pathway
8	SREBP signalling
9	Cori Cycle
10	Synthesis, Secretion, and Deacylation of Ghrelin
11	Signaling by Insulin receptor
12	Regulation of beta-cell development
13	Integration of energy metabolism
14	Folate Metabolism
15	Vitamin B12 Metabolism
16	Selenium Micronutrient Network

References

Top

REF 1

2005 approvals: Safety first. Nature Reviews Drug Discovery 5, 92-93 (February 2006).

REF 2

Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.

REF 3

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 4

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

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: 7572).

REF 6

ClinicalTrials.gov (NCT01792284) A Study of LY2605541 in Participants With Type 1 Diabetes Mellitus. U.S. National Institutes of Health.

REF 7

ClinicalTrials.gov (NCT02302716) A Study of LY2963016 Compared to LANTUS in Adult Participants With Type 2 Diabetes Mellitus. U.S. National Institutes of Health.

REF 8

ClinicalTrials.gov (NCT00411892) Effect of Inhaled Insulin (AERx iDMS) on Blood Glucose Control in Type 2 Diabetes. U.S. National Institutes of Health.

REF 9

ClinicalTrials.gov (NCT02273180) Comparison of SAR342434 to Humalog as the Rapid Acting Insulin in Adult Patients With Type 1 Diabetes Mellitus Also Using Insulin Glargine. U.S. National Institutes of Health.

REF 10

Clinical pipeline report, company report or official report of Sanofi.

REF 11

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 12

ClinicalTrials.gov (NCT02470039) Trial to Compare NNC0123-0000-0338 in a Tablet Formulation and Insulin Glargine in Subjects With Type 2 Diabetes Currently Treated With Oral Antidiabetic Therapy.

REF 13

ClinicalTrials.gov (NCT01053728) Study of How Single Rising Doses of SAR161271 Are Absorbed and Act in Patients With Type 1 Diabetes Mellitus (T1DM). 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 800033163)

REF 15

ClinicalTrials.gov (NCT00057499) Evaluation of a Diabetes Vaccine in Newly Diagnosed Diabetics. U.S. National Institutes of Health.

REF 16

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024901)

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 800037853)

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 800036594)

REF 19

Proinsulin peptide immunotherapy in type 1 diabetes: report of a first-in-man Phase I safety study. Clin Exp Immunol. 2009 Feb;155(2):156-65.

REF 20

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011773)

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 800004396)

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 800013224)

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 800015749)

REF 24

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

REF 25

LY2605541--a preferential hepato-specific insulin analogue. Diabetes. 2014 Feb;63(2):390-2.

REF 26

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.

REF 27

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.

REF 28

Inhaled Insulin: Promises and Concerns. J Diabetes Sci Technol. 2008 March; 2(2): 311-315.

REF 29

Biosimilar insulins: a European perspective. Diabetes Obes Metab. 2015 May; 17(5): 445-451.

REF 30

U300, a novel long-acting insulin formulation. Expert Opin Biol Ther. 2014 Dec;14(12):1849-60.

REF 31

Clinical pipeline report, company report or official report of Mercia Pharma Inc.

REF 32

ClinicalTrials.gov (NCT01334034) Safety of NNC 0123-0000-0338 in Healthy Subjects. U.S. National Institutes of Health.

REF 33

Clinical pipeline report, company report or official report of sanofi-aventis.

REF 34

The future of basal insulin supplementation. Diabetes Technol Ther. 2011 Jun;13 Suppl 1:S103-8.

REF 35

Prevention of Type 1 Diabetes Mellitus using a Novel Vaccine. Ther Adv Endocrinol Metab. 2011 February; 2(1): 9-16.

REF 36

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

REF 37

Company report (Novonordisk)

REF 38

Novo Nordisk increased operating profit in local currencies by 15% in the first quarter of 2014

REF 39

Synergistic antihyperglycemic effects between plant-derived oleanolic acid and insulin in streptozotocin-induced diabetic rats. Ren Fail. 2010;32(7):832-9.

REF 40

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.

REF 41

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.

REF 42

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.

REF 43

Degludec insulin: A novel basal insulin. Indian J Endocrinol Metab. 2011 July; 15(Suppl1): S12-S16.

REF 44

ClinicalTrials.gov (NCT01120912) Safety and Efficacy of Single Administration of Oshadi Oral Insulin in Type I Diabetes Patients. U.S. National Institutes of Health.

REF 45

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.

REF 46

Structural characterization of insulin NPH formulations. Eur J Pharm Sci. 2007 Apr;30(5):414-23.

REF 47

Computational and structural evidence for neurotransmitter-mediated modulation of the oligomeric states of human insulin in storage granules. J Biol Chem. 2017 May 19;292(20):8342-8355.

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