Target Information

Target General Information

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Target ID

T30085 (Former ID: TTDNC00579)

Target Name

Sodium/glucose cotransporter 2 (SGLT2)

Synonyms

Solute carrier family 5 member 2; Na(+)/glucose cotransporter 2; Low affinity sodium-glucose cotransporter

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Gene Name

SLC5A2

Target Type

Successful target

[1]

Disease

[+] 3 Target-related Diseases

Diabetes mellitus [ICD-11: 5A10]

Heart failure [ICD-11: BD10-BD1Z]

Type 2 diabetes mellitus [ICD-11: 5A11]

Function

Has a Na(+) to glucose coupling ratio of 1:1. Sodium-dependent glucose transporter.

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BioChemical Class

Solute:sodium symporter

UniProt ID

SC5A2_HUMAN

Sequence

MEEHTEAGSAPEMGAQKALIDNPADILVIAAYFLLVIGVGLWSMCRTNRGTVGGYFLAGR
SMVWWPVGASLFASNIGSGHFVGLAGTGAASGLAVAGFEWNALFVVLLLGWLFAPVYLTA
GVITMPQYLRKRFGGRRIRLYLSVLSLFLYIFTKISVDMFSGAVFIQQALGWNIYASVIA
LLGITMIYTVTGGLAALMYTDTVQTFVILGGACILMGYAFHEVGGYSGLFDKYLGAATSL
TVSEDPAVGNISSFCYRPRPDSYHLLRHPVTGDLPWPALLLGLTIVSGWYWCSDQVIVQR
CLAGKSLTHIKAGCILCGYLKLTPMFLMVMPGMISRILYPDEVACVVPEVCRRVCGTEVG
CSNIAYPRLVVKLMPNGLRGLMLAVMLAALMSSLASIFNSSSTLFTMDIYTRLRPRAGDR
ELLLVGRLWVVFIVVVSVAWLPVVQAAQGGQLFDYIQAVSSYLAPPVSAVFVLALFVPRV
NEQGAFWGLIGGLLMGLARLIPEFSFGSGSCVQPSACPAFLCGVHYLYFAIVLFFCSGLL
TLTVSLCTAPIPRKHLHRLVFSLRHSKEEREDLDADEQQGSSLPVQNGCPESAMEMNEPQ
APAPSLFRQCLLWFCGMSRGGVGSPPPLTQEEAAAAARRLEDISEDPSWARVVNLNALLM
MAVAVFLWGFYA

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3D Structure

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AlphaFold

HIT2.0 ID

T48DQY

Drugs and Modes of Action

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Approved Drug(s)

[+] 4 Approved Drugs

Canagliflozin

Drug Info

Approved

Type-2 diabetes

[4], [5], [6], [7]

Dapagliflozin

Drug Info

Approved

Type-2 diabetes

[8], [1], [4]

Empagliflozin

Drug Info

Approved

Type-1 diabetes

[9], [1]

PF-04971729

Drug Info

Approved

Type-2 diabetes

[10]

Clinical Trial Drug(s)

[+] 5 Clinical Trial Drugs

ASP1941

Drug Info

Phase 3

Liver disease

[11]

AVE-2268

Drug Info

Phase 2

Diabetic complication

[17]

YM-543

Drug Info

Phase 2

Type-2 diabetes

[18]

BI-44847

Drug Info

Phase 1

Type-2 diabetes

[19]

EGT-0001474

Drug Info

Phase 1

Type-2 diabetes

[20]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

TS-033

Drug Info

Discontinued in Phase 2

Diabetic complication

[21]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 11 Modulator drugs

Canagliflozin

Drug Info

[6], [7], [22]

Dapagliflozin

Drug Info

[1], [22]

Empagliflozin

Drug Info

[1]

PF-04971729

Drug Info

[23]

ASP1941

Drug Info

[24], [25]

AVE-2268

Drug Info

[26]

YM-543

Drug Info

[27]

BI-44847

Drug Info

[28]

EGT-0001474

Drug Info

[29]

TS-033

Drug Info

[30]

Empagli ozin

Drug Info

[1]

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: Empagliflozin

Ligand Info

Structure Description

Structure of human SGLT2-MAP17 complex bound with empagliflozin

PDB:7VSI

Method

Electron microscopy

Resolution

2.95 Å

Mutation

[31]

PDB Sequence

DNPADILVIA

³⁰

AYFLLVIGVG

⁴⁰

LWSMCRTNRG

⁵⁰

TVGGYFLAGR

⁶⁰

SMVWWPVGAS

⁷⁰

LFASNIGSGH

⁸⁰

FVGLAGTGAA

⁹⁰

SGLAVAGFEW

¹⁰⁰

NALFVVLLLG

¹¹⁰

WLFAPVYLTA

¹²⁰

GVITMPQYLR

¹³⁰

KRFGGRRIRL

¹⁴⁰

YLSVLSLFLY

¹⁵⁰

IFTKISVDMF

¹⁶⁰

SGAVFIQQAL

¹⁷⁰

GWNIYASVIA

¹⁸⁰

LLGITMIYTV

¹⁹⁰

TGGLAALMYT

²⁰⁰

DTVQTFVILG

²¹⁰

GACILMGYAF

²²⁰

HEVGGYSGLF

²³⁰

DKYLGAATSL

²⁴⁰

TVSEDPAVGN

²⁵⁰

ISSFCYRPRP

²⁶⁰

DSYHLLRHPV

²⁷⁰

TGDLPWPALL

²⁸⁰

LGLTIVSGWY

²⁹⁰

WCSDQVIVQR

³⁰⁰

CLAGKSLTHI

³¹⁰

KAGCILCGYL

³²⁰

KLTPMFLMVM

³³⁰

PGMISRILYP

³⁴⁰

DEVACVVPEV

³⁵⁰

CRRVCGTEVG

³⁶⁰

CSNIAYPRLV

³⁷⁰

VKLMPNGLRG

³⁸⁰

LMLAVMLAAL

³⁹⁰

MSSLASIFNS

⁴⁰⁰

SSTLFTMDIY

⁴¹⁰

TRLRPRAGDR

⁴²⁰

ELLLVGRLWV

⁴³⁰

VFIVVVSVAW

⁴⁴⁰

LPVVQAAQGG

⁴⁵⁰

QLFDYIQAVS

⁴⁶⁰

SYLAPPVSAV

⁴⁷⁰

FVLALFVPRV

⁴⁸⁰

NEQGAFWGLI

⁴⁹⁰

GGLLMGLARL

⁵⁰⁰

IPEFSFGSGS

⁵¹⁰

CVQPSACPAF

⁵²⁰

LCGVHYLYFA

⁵³⁰

IVLFFCSGLL

⁵⁴⁰

TLTVSLCTAP

⁵⁵⁰

IPRKHLHRLV

⁵⁶⁰

FSLRHSKEER

⁵⁷⁰

EDLDEDISED

⁶⁴⁶

PSWARVVNLN

⁶⁵⁶

ALLMMAVAVF

⁶⁶⁶

LWGFYA

Residue

Distance (Å)

ASN75

3.274

GLY79

4.021

HIS80

3.181

GLY83

3.564

LEU84

3.413

THR87

3.408

VAL95

3.319

PHE98

2.403

GLU99

3.242

ALA102

3.736

THR153

4.471

VAL157

3.728

LEU274

3.838

Residue

Distance (Å)

LEU283

4.153

VAL286

3.452

SER287

2.574

TYR290

3.763

TRP291

3.896

LYS321

3.221

PHE453

3.753

ASP454

2.988

ILE456

4.960

GLN457

3.255

SER460

4.386

TYR526

3.975

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 Similarity Proteins

Different Human System Profiles of Target

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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 Similarity Proteins

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

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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Reactome

[+] 3 Reactome Pathways

Hexose transport

Na+-dependent glucose transporters

Inositol transporters

WikiPathways

[+] 3 WikiPathways

NRF2 pathway

Nuclear Receptors Meta-Pathway

Transport of glucose and other sugars, bile salts and organic acids, metal ions and amine compounds

References

Top

REF 1

2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.

REF 2

FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 216203.

REF 3

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2018

REF 4

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

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: 4582).

REF 6

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

REF 7

Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial. Metabolism. 2014 Oct;63(10):1296-303.

REF 8

REF 9

REF 10

2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.

REF 11

ClinicalTrials.gov (NCT01054092) A Study to Assess the Long-term Safety and Efficacy of ASP1941 in Japanese Diabetic Patients. U.S. National Institutes of Health.

REF 12

ClinicalTrials.gov (NCT00800176) A Dose-Finding Study of RO4998452 in Patients With Diabetes Mellitus. U.S. National Institutes of Health.

REF 13

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021813)

REF 14

ClinicalTrials.gov (NCT01824264) Dose-finding Study of LIK066 Compared With Placebo or Sitagliptin to Evaluate Change in HbA1c in Patients With Diabetes. U.S. National Institutes of Health.

REF 15

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

REF 16

ClinicalTrials.gov (NCT04956263) A Comparison of Postprandial Glucose After a Mixed Meal Tolerance Test, and the Metabolic Effects of Insulin Withdrawal in a Crossover Study of the Dual Systemic SGLT1 and SGLT2 Inhibitor YG1699, and the Selective SGLT2 Inhibitor Dapagliflozin in Subjects With Type 1 Diabetes. U.S.National Institutes of Health.

REF 17

ClinicalTrials.gov (NCT00361738) Dose-Ranging Study Evaluating AVE2268 in Patients With Type 2 Diabetes Not Adequately Controlled by a Metformin Treatment. U.S. National Institutes of Health.

REF 18

ClinicalTrials.gov (NCT00454233) A Safety and Efficacy Study With YM543 in Type 2 Diabetes Mellitus Subjects. U.S. National Institutes of Health.

REF 19

ClinicalTrials.gov (NCT02211937) Relative Oral Bioavailability of BI 44847 as Suspension Compared to Tablet and the Influence of Food Anf of BI 44847 as Solution Compared to Tablet in Healthy Male Volunteers. U.S. National Institutes of Health.

REF 20

ClinicalTrials.gov (NCT00854113) Study to Determine the Safety, Tolerability, and Pharmacokinetic (PK) Profile of EGT0001474 in Healthy Volunteers. U.S. National Institutes of Health.

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 800021799)

REF 22

Canagliflozin-current status in the treatment of type 2 diabetes mellitus with focus on clinical trial data.World J Diabetes.2014 Jun 15;5(3):399-406.

REF 23

Dose-ranging efficacy and safety study of ertugliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes on a background of metformin.Diabetes Obes Metab.2015 Jun;17(6):591-8.

REF 24

Ipragliflozin: A novel sodium-glucose cotransporter 2 inhibitor developed in Japan.World J Diabetes.2015 Feb 15;6(1):136-44.

REF 25

Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin: a dose-finding study.Diabetes Obes Metab. 2013 May;15(5):403-9.

REF 26

Effects of AVE2268, a substituted glycopyranoside, on urinary glucose excretion and blood glucose in mice and rats. Arzneimittelforschung. 2008;58(11):574-80.

REF 27

Pharmacological Characterization of YM543, a Newly Synthesized, Orally Active SGLT2 Selective Inhibitor. Endocr Res. 2013 Aug;38(3):168-183.

REF 28

Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes

REF 29

PhRMA report

REF 30

Company report (Taisho)

REF 31

Structural basis of inhibition of the human SGLT2-MAP17 glucose transporter. Nature. 2022 Jan;601(7892):280-284.

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