Molecule Information

General Information of the Molecule (ID: Mol00092)

• Name: Isocitrate dehydrogenase NADP 2 (IDH2) ,Homo sapiens
• Synonyms: IDH; ICD-M; IDP; NADP(+)-specific ICDH; Oxalosuccinate decarboxylase
• Molecule Type: Protein
• Gene Name: IDH2
• Gene ID: 3418
• Location: chr15:90083045-90102477[-]
• Sequence:
  MAGYLRVVRSLCRASGSRPAWAPAALTAPTSQEQPRRHYADKRIKVAKPVVEMDGDEMTR
  IIWQFIKEKLILPHVDIQLKYFDLGLPNRDQTDDQVTIDSALATQKYSVAVKCATITPDE
  ARVEEFKLKKMWKSPNGTIRNILGGTVFREPIICKNIPRLVPGWTKPITIGRHAHGDQYK
  ATDFVADRAGTFKMVFTPKDGSGVKEWEVYNFPAGGVGMGMYNTDESISGFAHSCFQYAI
  QKKWPLYMSTKNTILKAYDGRFKDIFQEIFDKHYKTDFDKNKIWYEHRLIDDMVAQVLKS
  SGGFVWACKNYDGDVQSDILAQGFGSLGLMTSVLVCPDGKTIEAEAAHGTVTRHYREHQK
  GRPTSTNPIASIFAWTRGLEHRGKLDGNQDLIRFAQMLEKVCVETVESGAMTKDLAGCIH
  GLSNVKLNEHFLNTTDFLDTIKSNLDRALGRQ
• Function: Plays a role in intermediary metabolism and energy production. It may tightly associate or interact with the pyruvate dehydrogenase complex.
• Uniprot ID: IDHP_HUMAN
• Ensembl ID: ENSG00000182054
• HGNC ID: HGNC:5383

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Dichloroacetate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioblastoma [ICD-11: 2A00.02] [1]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Resistant Drug: Dichloroacetate
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.21E-01; Fold-change: 9.39E-03; Z-score: 1.55E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DBTRG cells; Brain; Homo sapiens (Human); CVCL_1169
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: Colorimetric SRB assay
• Mechanism Description: The potential of miR-144 overexpression to reduce GB cell malignancy, both by decreasing Cell migration and invasion abilities and by sensitizing resistant tumor cells to chemotherapy, paving the way to a novel and more effective GB therapy.

Cytarabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Cytarabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/Akt/mTOR signaling pathway; Regulation; N.A.
• In Vitro Model: HL-60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vivo Model: SPF-grade (BALB/C) nude mice model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Glycolysis metabolic enzyme assay; Flow cytometry; Western blot assay; Transcriptome sequencingc assay
• Experiment for Drug Resistance: Cell proliferation assay; Drug sensitivity testing
• Mechanism Description: OE-IDH2 in AML cells, enhances resistance to the Ara-C, promotes cell proliferation and glycolysis, and inhibits apoptosis. KD-IDH2 exhibits opposite effects. Both IDH2 mutations and OE-IDH2 produce similar effects on these cellular processes. The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells. Transcriptome sequencing results indicate an enrichment of the PI3K/Akt signaling pathway in IDH2-mutant AML cells. BEZ235 significantly inhibits the expression of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), mTOR, glycolytic metabolism, and Ara-C resistance both in vitro and in vivo. Overexpression and mutation of IDH2 coordinate with the Warburg effect through the PI3K/Akt/mTOR pathway to promote Ara-C resistance in AML.

Clinical Trial Drug(s) 1 drug(s) in total

Enasidenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Hematologic Cancer [ICD-11: MG24.Y] [3]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.93 Å; PDB: 5GIS
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.10 Å; PDB: 5SVN

RMSD: 1.13; TM score: 0.29352; Amino acid change: R172K

• Experimental Note: Identified from the Human Clinical Data

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [4]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.93 Å; PDB: 5GIS
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.10 Å; PDB: 5SVN

RMSD: 1.13; TM score: 0.29352; Amino acid change: R172K

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vivo Model: Acute myeloid leukemia xenograft mouse model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [4]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R140Q (c.419G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.10 Å; PDB: 5SVN
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.54 Å; PDB: 5I95

RMSD: 0.33; TM score: 0.99798; Amino acid change: R140Q

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vivo Model: Acute myeloid leukemia xenograft mouse model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Disease Class: Hematologic Cancer [ICD-11: MG24.Y] [3]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R140K (c.418_419delCGinsAA)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [4]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R140G (c.418C>G)
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [4]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R140W (c.418C>T)
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [4]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R140L (c.419G>T)
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [4]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R172G (c.514A>G)
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [4]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R172W (c.514A>T)
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [4]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R172M (c.515G>T)
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [4]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R172S (c.516G>C)
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01] [5]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.93 Å; PDB: 5GIS
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.10 Å; PDB: 5SVN

RMSD: 1.13; TM score: 0.29352; Amino acid change: R172K

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: TF-1a cells; Bone marrow; Homo sapiens (Human); CVCL_3608
• In Vitro Model: IDH2 cells; Ovary; Homo sapiens (Human); CVCL_D3DY
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Mechanism Description: Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [5]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.93 Å; PDB: 5GIS
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.10 Å; PDB: 5SVN

RMSD: 1.13; TM score: 0.29352; Amino acid change: R172K

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: TF-1a cells; Bone marrow; Homo sapiens (Human); CVCL_3608
• In Vitro Model: IDH2 cells; Ovary; Homo sapiens (Human); CVCL_D3DY
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Mechanism Description: Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.

Disease Class: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01] [5]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: Enasidenib
• Molecule Alteration: Missense mutation; p.R140Q (c.419G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.10 Å; PDB: 5SVN
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.54 Å; PDB: 5I95

RMSD: 0.33; TM score: 0.99798; Amino acid change: R140Q

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: TF-1a cells; Bone marrow; Homo sapiens (Human); CVCL_3608
• In Vitro Model: IDH2 cells; Ovary; Homo sapiens (Human); CVCL_D3DY
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Mechanism Description: Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.

Preclinical Drug(s) 1 drug(s) in total

AGI-6780

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [6]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: AGI-6780
• Molecule Alteration: Missense mutation; p.R140Q (c.419G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.10 Å; PDB: 5SVN
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.54 Å; PDB: 5I95

RMSD: 0.33; TM score: 0.99798; Amino acid change: R140Q

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Blood; N.A.
• Mechanism Description: The missense mutation p.R140Q (c.419G>A) in gene IDH2 cause the sensitivity of AGI-6780 by aberration of the drug's therapeutic target

Investigative Drug(s) 1 drug(s) in total

IDH2 inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [3]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: IDH2 inhibitors
• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.93 Å; PDB: 5GIS
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.10 Å; PDB: 5SVN

RMSD: 1.13; TM score: 0.29352; Amino acid change: R172K

• Experimental Note: Identified from the Human Clinical Data

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [3]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: IDH2 inhibitors
• Molecule Alteration: Missense mutation; p.R140Q (c.419G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.10 Å; PDB: 5SVN
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.54 Å; PDB: 5I95

RMSD: 0.33; TM score: 0.99798; Amino acid change: R140Q

• Experimental Note: Identified from the Human Clinical Data

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Brain cancer [ICD-11: 2A00]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Nervous tissue
• The Specified Disease: Brain cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.21E-01; Fold-change: -6.37E-02; Z-score: -1.02E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.29E-01; Fold-change: 3.97E-01; Z-score: 6.63E-01
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.86E-01; Fold-change: -4.82E-02; Z-score: -1.50E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.48E-01; Fold-change: 2.57E-01; Z-score: 5.98E-01

Acute myeloid leukemia [ICD-11: 2A60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Bone marrow
• The Specified Disease: Acute myeloid leukemia
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.06E-02; Fold-change: 1.15E-01; Z-score: 2.41E-01

References

• Ref 1: MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy. Hum Mol Genet. 2019 Aug 15;28(16):2738-2751. doi: 10.1093/hmg/ddz099.
• Ref 2: Isocitrate dehydrogenase 2 mutation promotes cytarabine resistance in acute myeloid leukemia by Warburg effect. Hematol Oncol. 2024 Nov;42(6):e3316.
• Ref 3: Abstract CT103: Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-0280.
• Ref 4: Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemiaBlood. 2017 Aug 10;130(6):722-731. doi: 10.1182/blood-2017-04-779405. Epub 2017 Jun 6.
• Ref 5: AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 MutationsCancer Discov. 2017 May;7(5):478-493. doi: 10.1158/2159-8290.CD-16-1034. Epub 2017 Feb 13.
• Ref 6: Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiationScience. 2013 May 3;340(6132):622-6. doi: 10.1126/science.1234769. Epub 2013 Apr 4.