Molecule Information

General Information of the Molecule (ID: Mol00423)

• Name: Oxalosuccinate decarboxylase (IDH1) ,Homo sapiens
• Synonyms: IDH; Cytosolic NADP-isocitrate dehydrogenase; IDP; NADP(+)-specific ICDH; Oxalosuccinate decarboxylase; PICD
• Molecule Type: Protein
• Gene Name: IDH1
• Gene ID: 3417
• Location: chr2:208236229-208266074[-]
• Sequence:
  MSKKISGGSVVEMQGDEMTRIIWELIKEKLIFPYVELDLHSYDLGIENRDATNDQVTKDA
  AEAIKKHNVGVKCATITPDEKRVEEFKLKQMWKSPNGTIRNILGGTVFREAIICKNIPRL
  VSGWVKPIIIGRHAYGDQYRATDFVVPGPGKVEITYTPSDGTQKVTYLVHNFEEGGGVAM
  GMYNQDKSIEDFAHSSFQMALSKGWPLYLSTKNTILKKYDGRFKDIFQEIYDKQYKSQFE
  AQKIWYEHRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDSVAQGYGSLGMMTSVLVCPDG
  KTVEAEAAHGTVTRHYRMYQKGQETSTNPIASIFAWTRGLAHRAKLDNNKELAFFANALE
  EVSIETIEAGFMTKDLAACIKGLPNVQRSDYLNTFEFMDKLGENLKIKLAQAKL
• Uniprot ID: IDHC_HUMAN
• Ensembl ID: ENSG00000138413
• HGNC ID: HGNC:5382

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) 6 drug(s) in total

Azacitidine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: FGFR-tacc positive glioblastoma [1]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: Azacitidine
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• In Vivo Model: Female athymic nude mouse (NCI-Frederick) model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Tumor volume measurement assay

Bevacizumab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Brain glioma [2]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Sensitive Drug: Bevacizumab
• Molecule Alteration: Missense mutation; p.R132S (c.394C>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• Mechanism Description: The missense mutation p.R132S (c.394C>A) in gene IDH1 cause the sensitivity of Bevacizumab by aberration of the drug's therapeutic target

Disease Class: Brain glioma [2]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Sensitive Drug: Bevacizumab
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• Mechanism Description: The missense mutation p.R132C (c.394C>T) in gene IDH1 cause the sensitivity of Bevacizumab by aberration of the drug's therapeutic target

Disease Class: Brain glioma [2]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Sensitive Drug: Bevacizumab
• Molecule Alteration: Missense mutation; p.R132L (c.395G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• Mechanism Description: The missense mutation p.R132L (c.395G>T) in gene IDH1 cause the sensitivity of Bevacizumab by aberration of the drug's therapeutic target

Ivosidenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Acute myeloid leukemia [3]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Ivosidenib
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Acute myeloid leukemia [3]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Ivosidenib
• Molecule Alteration: Missense mutation; p.R132S (c.394C>A)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Acute myeloid leukemia [3]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Ivosidenib
• Molecule Alteration: Missense mutation; p.R132G (c.394C>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Acute myeloid leukemia [3]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Ivosidenib
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Acute myeloid leukemia [3]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: Ivosidenib
• Molecule Alteration: Missense mutation; p.R132L (c.395G>T)
• Experimental Note: Identified from the Human Clinical Data

Rucaparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Solid tumour/cancer [4]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

Talazoparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Colon cancer [4]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Sensitive Drug: Talazoparib
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

Disease Class: Brain glioma [4]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Sensitive Drug: Talazoparib
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

Disease Class: Brain glioma [4]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Sensitive Drug: Talazoparib
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

Dichloroacetate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioblastoma [5]

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

Clinical Trial Drug(s) 3 drug(s) in total

Niraparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Solid tumour/cancer [4]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Niraparib
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

BAY1436032

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [6]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: BAY1436032
• Molecule Alteration: Missense mutation; p.R132S (c.394C>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HoxA9-IDH2R140Q cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH2172K cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132H cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132C cells; N.A.; .; N.A.
• In Vivo Model: mouse PDX model; Mus musculus
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: BAY1436032 inhibits proliferation and induces differentiation in primary human AML cells. BAY1436032 clears AML blasts in vivo and prolongs survival in PDX models of IDH1 mutant AML. BAY1436032 induces myeloid differentiation in IDH1 mutant AML PDX models in vivo and depletes leukemic stem cells by induction of myeloid differentiation and inhibition of cell cycle progression.

Disease Class: Acute myeloid leukemia [6]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: BAY1436032
• Molecule Alteration: Missense mutation; p.R132G (c.394C>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HoxA9-IDH2R140Q cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH2172K cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132H cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132C cells; N.A.; .; N.A.
• In Vivo Model: mouse PDX model; Mus musculus
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: BAY1436032 inhibits proliferation and induces differentiation in primary human AML cells. BAY1436032 clears AML blasts in vivo and prolongs survival in PDX models of IDH1 mutant AML. BAY1436032 induces myeloid differentiation in IDH1 mutant AML PDX models in vivo and depletes leukemic stem cells by induction of myeloid differentiation and inhibition of cell cycle progression.

Disease Class: Acute myeloid leukemia [6]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: BAY1436032
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HoxA9-IDH2R140Q cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH2172K cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132H cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132C cells; N.A.; .; N.A.
• In Vivo Model: mouse PDX model; Mus musculus
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: BAY1436032 inhibits proliferation and induces differentiation in primary human AML cells. BAY1436032 clears AML blasts in vivo and prolongs survival in PDX models of IDH1 mutant AML. BAY1436032 induces myeloid differentiation in IDH1 mutant AML PDX models in vivo and depletes leukemic stem cells by induction of myeloid differentiation and inhibition of cell cycle progression.

Disease Class: Acute myeloid leukemia [6]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: BAY1436032
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HoxA9-IDH2R140Q cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH2172K cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132H cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132C cells; N.A.; .; N.A.
• In Vivo Model: mouse PDX model; Mus musculus
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: BAY1436032 inhibits proliferation and induces differentiation in primary human AML cells. BAY1436032 clears AML blasts in vivo and prolongs survival in PDX models of IDH1 mutant AML. BAY1436032 induces myeloid differentiation in IDH1 mutant AML PDX models in vivo and depletes leukemic stem cells by induction of myeloid differentiation and inhibition of cell cycle progression.

Disease Class: Acute myeloid leukemia [6]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: BAY1436032
• Molecule Alteration: Missense mutation; p.R132L (c.395G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HoxA9-IDH2R140Q cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH2172K cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132H cells; N.A.; .; N.A.
• In Vitro Model: HoxA9-IDH1R132C cells; N.A.; .; N.A.
• In Vivo Model: mouse PDX model; Mus musculus
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: BAY1436032 inhibits proliferation and induces differentiation in primary human AML cells. BAY1436032 clears AML blasts in vivo and prolongs survival in PDX models of IDH1 mutant AML. BAY1436032 induces myeloid differentiation in IDH1 mutant AML PDX models in vivo and depletes leukemic stem cells by induction of myeloid differentiation and inhibition of cell cycle progression.

Berzosertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Solid tumour/cancer [4]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Berzosertib
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

Preclinical Drug(s) 9 drug(s) in total

AGI-5198

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: FGFR-tacc positive glioblastoma [7]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: AGI-5198
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TS676 cells; Brain; Homo sapiens (Human); CVCL_A5HX
• In Vitro Model: TS603 cells; Brain; Homo sapiens (Human); CVCL_A5HW
• In Vitro Model: TS516 cells; Brain; Homo sapiens (Human); CVCL_A5HY
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: Soft agar assay
• Mechanism Description: The missense mutation p.R132H (c.395G>A) in gene IDH1 cause the sensitivity of AGI-5198 by aberration of the drug's therapeutic target

Disease Class: Brain glioma [7]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Sensitive Drug: AGI-5198
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TS676 cells; Brain; Homo sapiens (Human); CVCL_A5HX
• In Vitro Model: TS603 cells; Brain; Homo sapiens (Human); CVCL_A5HW
• In Vitro Model: TS516 cells; Brain; Homo sapiens (Human); CVCL_A5HY
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: Soft agar assay
• Mechanism Description: The missense mutation p.R132C (c.394C>T) in gene IDH1 cause the sensitivity of AGI-5198 by aberration of the drug's therapeutic target

Disease Class: Brain glioma [7]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Sensitive Drug: AGI-5198
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TS676 cells; Brain; Homo sapiens (Human); CVCL_A5HX
• In Vitro Model: TS603 cells; Brain; Homo sapiens (Human); CVCL_A5HW
• In Vitro Model: TS516 cells; Brain; Homo sapiens (Human); CVCL_A5HY
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: Soft agar assay
• Mechanism Description: The missense mutation p.R132H (c.395G>A) in gene IDH1 cause the sensitivity of AGI-5198 by aberration of the drug's therapeutic target

AGI-5198/Metformin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Colorectal cancer [8]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: AGI-5198/Metformin
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis; gama-H2AX immunofluorescence staining and measurement
• Experiment for Drug Resistance: Colony formation assay

AGI-5198/Olaparib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Sarcoma [4]

• Resistant Disease: Sarcoma [ICD-11: 2C35.0]
• Resistant Drug: AGI-5198/Olaparib
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

AGI-5198/Talazoparib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Sarcoma [4]

• Resistant Disease: Sarcoma [ICD-11: 2C35.0]
• Resistant Drug: AGI-5198/Talazoparib
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

Disease Class: Solid tumour/cancer [4]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Resistant Drug: AGI-5198/Talazoparib
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

BPTES

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [9]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: BPTES
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: AML cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Manually cell counting assay

Disease Class: Brain glioma [10]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Sensitive Drug: BPTES
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Drug Resistance: 3H-thymidine incorporation assay
• Mechanism Description: The missense mutation p.R132H (c.395G>A) in gene IDH1 cause the sensitivity of BPTES by unusual activation of pro-survival pathway

Cisplatin/Talazoparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Solid tumour/cancer [4]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Cisplatin/Talazoparib
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

GSK321

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Acute myeloid leukemia [11]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: GSK321
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HT-1080 cells; Acetabulum; Homo sapiens (Human); CVCL_0317
• In Vivo Model: Male CD-1 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Diaphorase/resazurin coupled assay; Colony formation assay

IDH1 inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Brain glioma [7]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Sensitive Drug: IDH1 inhibitors
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TS676 cells; Brain; Homo sapiens (Human); CVCL_A5HX
• In Vitro Model: TS603 cells; Brain; Homo sapiens (Human); CVCL_A5HW
• In Vitro Model: TS516 cells; Brain; Homo sapiens (Human); CVCL_A5HY
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: Soft agar assay
• Mechanism Description: The missense mutation p.R132H (c.395G>A) in gene IDH1 cause the sensitivity of IDH1 inhibitors by aberration of the drug's therapeutic target

PARP inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Solid tumour/cancer [4]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PARP inhibitors
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

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

Temozolomide/Vandetanib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: FGFR-tacc positive glioblastoma [12]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Sensitive Drug: Temozolomide/Vandetanib
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• Experiment for Molecule Alteration: Multiplex array; Standard ELISA assay
• Experiment for Drug Resistance: Pharmacokinetics analysis

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: 7.42E-176; Fold-change: 1.87E+00; Z-score: 2.54E+00
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.08E-01; Fold-change: -1.90E-01; Z-score: -2.22E-01
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.47E-01; Fold-change: 2.98E-01; Z-score: 6.75E-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: 3.39E-07; Fold-change: 2.16E+00; Z-score: 3.41E+00

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: 2.34E-03; Fold-change: -5.35E-02; Z-score: -4.78E-02

Colon cancer [ICD-11: 2B90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Colon
• The Specified Disease: Colon cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.24E-32; Fold-change: -4.05E-01; Z-score: -1.35E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 4.33E-01; Fold-change: -1.34E-01; Z-score: -2.49E-01

Sarcoma [ICD-11: 2C35]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Muscle
• The Specified Disease: Sarcoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.89E-33; Fold-change: 4.54E-01; Z-score: 9.43E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.10E-06; Fold-change: 6.55E-01; Z-score: 8.02E+00

References

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• Ref 2: Correlation between IDH1 gene mutation status and survival of patients treated for recurrent gliomaAnticancer Res. 2011 Dec;31(12):4457-63.
• Ref 3: Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AMLN Engl J Med. 2018 Jun 21;378(25):2386-2398. doi: 10.1056/NEJMoa1716984. Epub 2018 Jun 2.
• Ref 4: 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivitySci Transl Med. 2017 Feb 1;9(375):eaal2463. doi: 10.1126/scitranslmed.aal2463.
• Ref 5: 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 6: Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivoLeukemia. 2017 Oct;31(10):2020-2028. doi: 10.1038/leu.2017.46. Epub 2017 Jan 31.
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• Ref 8: Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198Cancer Res. 2015 Nov 15;75(22):4790-802. doi: 10.1158/0008-5472.CAN-14-3603. Epub 2015 Sep 11.
• Ref 9: Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutationsExp Hematol. 2014 Apr;42(4):247-51. doi: 10.1016/j.exphem.2013.12.001. Epub 2013 Dec 11.
• Ref 10: Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1Cancer Res. 2010 Nov 15;70(22):8981-7. doi: 10.1158/0008-5472.CAN-10-1666. Epub 2010 Nov 2.
• Ref 11: New IDH1 mutant inhibitors for treatment of acute myeloid leukemiaNat Chem Biol. 2015 Nov;11(11):878-86. doi: 10.1038/nchembio.1930. Epub 2015 Oct 5.
• Ref 12: A Multicenter, Phase II, Randomized, Noncomparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly Diagnosed Glioblastoma PatientsClin Cancer Res. 2015 Aug 15;21(16):3610-8. doi: 10.1158/1078-0432.CCR-14-3220. Epub 2015 Apr 24.