Target Information
Target General Information | Top | |||||
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Target ID |
T69563
(Former ID: TTDI02094)
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Target Name |
Oxalosuccinate decarboxylase (IDH1)
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Synonyms |
PICD; NADP(+)-specific ICDH; Isocitrate dehydrogenase [NADP] cytoplasmic; IDP; IDH; Cytosolic NADP-isocitrate dehydrogenase
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Gene Name |
IDH1
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | 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
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UniProt ID | ||||||
EC Number |
EC 1.1.1.42
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Sequence |
MSKKISGGSVVEMQGDEMTRIIWELIKEKLIFPYVELDLHSYDLGIENRDATNDQVTKDA
AEAIKKHNVGVKCATITPDEKRVEEFKLKQMWKSPNGTIRNILGGTVFREAIICKNIPRL VSGWVKPIIIGRHAYGDQYRATDFVVPGPGKVEITYTPSDGTQKVTYLVHNFEEGGGVAM GMYNQDKSIEDFAHSSFQMALSKGWPLYLSTKNTILKKYDGRFKDIFQEIYDKQYKSQFE AQKIWYEHRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDSVAQGYGSLGMMTSVLVCPDG KTVEAEAAHGTVTRHYRMYQKGQETSTNPIASIFAWTRGLAHRAKLDNNKELAFFANALE EVSIETIEAGFMTKDLAACIKGLPNVQRSDYLNTFEFMDKLGENLKIKLAQAKL Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
1 | Ivosidenib | Drug Info | Approved | Acute myeloid leukaemia | [1], [2] | |
2 | Olutasidenib | Drug Info | Approved | Acute myeloid leukaemia | [3] | |
Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | IDH305 | Drug Info | Phase 1 | Advanced malignancy | [2] | |
2 | LY3410738 | Drug Info | Phase 1 | Solid tumour/cancer | [4] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 4 Inhibitor drugs | + | ||||
1 | Ivosidenib | Drug Info | [1] | |||
2 | Olutasidenib | Drug Info | [3] | |||
3 | IDH305 | Drug Info | [2] | |||
4 | LY3410738 | Drug Info | [5] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Drug Binding Sites of Target | Top | |||||
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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 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGH132 HAYGDQYRAT142 DFVVPGPGKV152 EITYTPSDGT 162 QKVTYLVHNF172 EEGGGVAMGM182 YNQDKSIEDF192 AHSSFQMALS202 KGWPLYLSTK 212 NTILKKYDGR222 FKDIFQEIYD232 KQYKSQFEAQ242 KIWYEHRLID252 DMVAQAMKSE 262 GGFIWACKNY272 DGDVQSDSVA282 QGYGSLGMMT292 SVLVCPDGKT302 VEAEAAHGTV 312 TRHYRMYQKG322 QETSTNPIAS332 IFAWTRGLAH342 RAKLDNNKEL352 AFFANALEEV 362 SIETIEAGFM372 TKDLAACIKG382 LPNVQRSDYL392 NTFEFMDKLG402 ENLKIKLAQA 412 KL
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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 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGH132 HAYGDQYRAT142 DFVVPGPGKV152 EITYTPSDGT 162 QKVTYLVHNF172 EEGGGVAMGM182 YNQDKSIEDF192 AHSSFQMALS202 KGWPLYLSTK 212 NTILKKYDGR222 FKDIFQEIYD232 KQYKSQFEAQ242 KIWYEHRLID252 DMVAQAMKSE 262 GGFIWACKNY272 DGDVQSDSVA282 QGYGSLGMMT292 SVLVCPDGKT302 VEAEAAHGTV 312 TRHYRMYQKG322 QETSTNPIAS332 IFAWTRGLAH342 RAKLDNNKEL352 AFFANALEEV 362 SIETIEAGFM372 TKDLAACIKG382 LPNVQRSDYL392 NTFEFMDKLG402 ENLKIKLAQA 412 KLSLE
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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
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Click to View More Binding Site Information of This Target with Different Ligands |
Different Human System Profiles of Target | Top |
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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 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
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There is no similarity protein (E value < 0.005) for this target
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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.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Citrate cycle (TCA cycle) | hsa00020 | Affiliated Target |
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Class: Metabolism => Carbohydrate metabolism | Pathway Hierarchy | ||
Glutathione metabolism | hsa00480 | Affiliated Target |
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Class: Metabolism => Metabolism of other amino acids | Pathway Hierarchy | ||
Peroxisome | hsa04146 | Affiliated Target |
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Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy |
Degree | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 1.55E-05 |
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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 | Top |
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Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 9 KEGG Pathways | + | ||||
1 | Citrate cycle (TCA cycle) | |||||
2 | Glutathione metabolism | |||||
3 | Metabolic pathways | |||||
4 | Biosynthesis of antibiotics | |||||
5 | Carbon metabolism | |||||
6 | 2-Oxocarboxylic acid metabolism | |||||
7 | Biosynthesis of amino acids | |||||
8 | Peroxisome | |||||
9 | Central carbon metabolism in cancer | |||||
NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
1 | FSH Signaling Pathway | |||||
Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
1 | Warburg Effect | |||||
WikiPathways | [+] 7 WikiPathways | + | ||||
1 | TCA Cycle and PDHc | |||||
2 | miR-targeted genes in squamous cell - TarBase | |||||
3 | miR-targeted genes in lymphocytes - TarBase | |||||
4 | miR-targeted genes in leukocytes - TarBase | |||||
5 | miR-targeted genes in epithelium - TarBase | |||||
6 | Peroxisomal lipid metabolism | |||||
7 | Glutathione metabolism |
References | Top | |||||
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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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