Target Information

Target General Information

Target ID

T69563 (Former ID: TTDI02094)

Target Name

Oxalosuccinate decarboxylase (IDH1)

Synonyms

PICD; NADP(+)-specific ICDH; Isocitrate dehydrogenase [NADP] cytoplasmic; IDP; IDH; Cytosolic NADP-isocitrate dehydrogenase

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Gene Name

IDH1

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Acute myeloid leukaemia [ICD-11: 2A60]

Function

Catalyses the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG).

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BioChemical Class

Short-chain dehydrogenases reductase

UniProt ID

IDHC_HUMAN

EC Number

EC 1.1.1.42

Sequence

MSKKISGGSVVEMQGDEMTRIIWELIKEKLIFPYVELDLHSYDLGIENRDATNDQVTKDA
AEAIKKHNVGVKCATITPDEKRVEEFKLKQMWKSPNGTIRNILGGTVFREAIICKNIPRL
VSGWVKPIIIGRHAYGDQYRATDFVVPGPGKVEITYTPSDGTQKVTYLVHNFEEGGGVAM
GMYNQDKSIEDFAHSSFQMALSKGWPLYLSTKNTILKKYDGRFKDIFQEIYDKQYKSQFE
AQKIWYEHRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDSVAQGYGSLGMMTSVLVCPDG
KTVEAEAAHGTVTRHYRMYQKGQETSTNPIASIFAWTRGLAHRAKLDNNKELAFFANALE
EVSIETIEAGFMTKDLAACIKGLPNVQRSDYLNTFEFMDKLGENLKIKLAQAKL

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3D Structure

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PDB

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Ivosidenib

Drug Info

Approved

Acute myeloid leukaemia

[1], [2]

Olutasidenib

Drug Info

Approved

Acute myeloid leukaemia

[3]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

IDH305

Drug Info

Phase 1

Advanced malignancy

[2]

LY3410738

Drug Info

Phase 1

Solid tumour/cancer

[4]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 4 Inhibitor drugs

Ivosidenib

Drug Info

[1]

Olutasidenib

Drug Info

[3]

IDH305

Drug Info

[2]

LY3410738

Drug Info

[5]

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: AG-881

Ligand Info

Structure Description

Crystal Structures of IDH1 R132H in complex with AG-881

PDB:6ADG

Method

X-ray diffraction

Resolution

3.00 Å

Mutation

Yes

[6]

PDB Sequence

KKISGGSVVE

¹²

MQGDEMTRII

²²

WELIKEKLIF

³²

PYVELDLHSY

⁴²

DLGIENRDAT

⁵²

NDQVTKDAAE

⁶²

AIKKHNVGVK

⁷²

CATITPDEKR

⁸²

VEEFKLKQMW

⁹²

KSPNGTIRNI

¹⁰²

LGGTVFREAI

¹¹²

ICKNIPRLVS

¹²²

GWVKPIIIGH

¹³²

HAYGDQYRAT

¹⁴²

DFVVPGPGKV

¹⁵²

EITYTPSDGT

¹⁶²

QKVTYLVHNF

¹⁷²

EEGGGVAMGM

¹⁸²

YNQDKSIEDF

¹⁹²

AHSSFQMALS

²⁰²

KGWPLYLSTK

²¹²

NTILKKYDGR

²²²

FKDIFQEIYD

²³²

KQYKSQFEAQ

²⁴²

KIWYEHRLID

²⁵²

DMVAQAMKSE

²⁶²

GGFIWACKNY

²⁷²

DGDVQSDSVA

²⁸²

QGYGSLGMMT

²⁹²

SVLVCPDGKT

³⁰²

VEAEAAHGTV

³¹²

TRHYRMYQKG

³²²

QETSTNPIAS

³³²

IFAWTRGLAH

³⁴²

RAKLDNNKEL

³⁵²

AFFANALEEV

³⁶²

SIETIEAGFM

³⁷²

TKDLAACIKG

³⁸²

LPNVQRSDYL

³⁹²

NTFEFMDKLG

⁴⁰²

ENLKIKLAQA

⁴¹²

Residue

Distance (Å)

TRP124

2.903

ILE251

4.526

VAL255

3.617

ALA258

3.736

MET259

2.717

TRP267

3.884

Residue

Distance (Å)

TYR272

4.128

ASP273

2.469

VAL276

3.758

GLN277

3.016

SER280

3.254

VAL281

3.744

Ligand Name: FT-2102

Ligand Info

Structure Description

Crystal structure of IDH1 R132H mutant in complex with FT-2102

PDB:6U4J

Method

X-ray diffraction

Resolution

2.11 Å

Mutation

Yes

[7]

PDB Sequence

KKISGGSVVE

¹²

MQGDEMTRII

²²

WELIKEKLIF

³²

PYVELDLHSY

⁴²

DLGIENRDAT

⁵²

NDQVTKDAAE

⁶²

AIKKHNVGVK

⁷²

CATITPDEKR

⁸²

VEEFKLKQMW

⁹²

KSPNGTIRNI

¹⁰²

LGGTVFREAI

¹¹²

ICKNIPRLVS

¹²²

GWVKPIIIGH

¹³²

HAYGDQYRAT

¹⁴²

DFVVPGPGKV

¹⁵²

EITYTPSDGT

¹⁶²

QKVTYLVHNF

¹⁷²

EEGGGVAMGM

¹⁸²

YNQDKSIEDF

¹⁹²

AHSSFQMALS

²⁰²

KGWPLYLSTK

²¹²

NTILKKYDGR

²²²

FKDIFQEIYD

²³²

KQYKSQFEAQ

²⁴²

KIWYEHRLID

²⁵²

DMVAQAMKSE

²⁶²

GGFIWACKNY

²⁷²

DGDVQSDSVA

²⁸²

QGYGSLGMMT

²⁹²

SVLVCPDGKT

³⁰²

VEAEAAHGTV

³¹²

TRHYRMYQKG

³²²

QETSTNPIAS

³³²

IFAWTRGLAH

³⁴²

RAKLDNNKEL

³⁵²

AFFANALEEV

³⁶²

SIETIEAGFM

³⁷²

TKDLAACIKG

³⁸²

LPNVQRSDYL

³⁹²

NTFEFMDKLG

⁴⁰²

ENLKIKLAQA

⁴¹²

KLSLE

Residue

Distance (Å)

ARG109

2.897

GLU110

3.994

ALA111

3.540

ILE113

3.639

ARG119

3.942

LEU120

3.050

VAL121

4.298

TRP124

3.684

LYS126

4.845

PRO127

3.440

ILE128

2.915

Residue

Distance (Å)

ILE129

4.788

ILE130

3.629

VAL255

4.884

ALA258

3.727

MET259

3.421

TRP267

3.481

ASP279

2.767

VAL281

3.425

ALA282

3.488

TYR285

3.187

MET291

3.782

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
Citrate cycle (TCA cycle)	hsa00020	Affiliated Target
Class: Metabolism => Carbohydrate metabolism	Pathway Hierarchy
Glutathione metabolism	hsa00480	Affiliated Target
Class: Metabolism => Metabolism of other amino acids	Pathway Hierarchy
Peroxisome	hsa04146	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy

Degree	8	Degree centrality	8.59E-04	Betweenness centrality	1.55E-05
Closeness centrality	1.72E-01	Radiality	1.27E+01	Clustering coefficient	5.36E-01
Neighborhood connectivity	1.26E+01	Topological coefficient	3.05E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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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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KEGG Pathway

[+] 9 KEGG Pathways

Citrate cycle (TCA cycle)

Glutathione metabolism

Metabolic pathways

Biosynthesis of antibiotics

Carbon metabolism

2-Oxocarboxylic acid metabolism

Biosynthesis of amino acids

Peroxisome

Central carbon metabolism in cancer

NetPath Pathway

[+] 1 NetPath Pathways

FSH Signaling Pathway

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Warburg Effect

WikiPathways

[+] 7 WikiPathways

TCA Cycle and PDHc

miR-targeted genes in squamous cell - TarBase

miR-targeted genes in lymphocytes - TarBase

miR-targeted genes in leukocytes - TarBase

miR-targeted genes in epithelium - TarBase

Peroxisomal lipid metabolism

Glutathione metabolism

References

Top

REF 1

2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.

REF 2

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

REF 3

FDA Approved Drug Products from FDA Official Website. 2022. Application Number: 215814.

REF 4

ClinicalTrials.gov (NCT04521686) Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 Mutations. U.S. National Institutes of Health.

REF 5

LY3410738, a novel inhibitor of mutant IDH1 is more effective than Ivosidenib and potentiates antileukemic activity of standard chemotherapy in preclinical models of acute myeloid leukemia (AML). Cancer Res 2020;80(16 Suppl):Abstract nr 6417.

REF 6

Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2. Biochem Biophys Res Commun. 2018 Sep 18;503(4):2912-2917.

REF 7

Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor. J Med Chem. 2020 Feb 27;63(4):1612-1623.

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