Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTQA4PB)

• DOT Name: Isocitrate dehydrogenase , mitochondrial (IDH2)
• Synonyms: IDH; EC 1.1.1.42; ICD-M; IDP; NADP(+)-specific ICDH; Oxalosuccinate decarboxylase
• Gene Name: IDH2
• Related Disease:
  Mitochondrial disease
  Angioimmunoblastic T-cell Lymphoma
  Cardiomyopathy
  Cholangiocarcinoma
  Colorectal neoplasm
  D-2-hydroxyglutaric aciduria 2
  Glioma susceptibility 1
  Head-neck squamous cell carcinoma
  Hypertrophic cardiomyopathy
  Intrahepatic cholangiocarcinoma
  Kidney failure
  Malignant glioma
  Melanoma
  Osteoporosis
  Plasma cell myeloma
  Primary cutaneous peripheral T-cell lymphoma not otherwise specified
  Promyelocytic leukaemia
  Breast carcinoma
  Hepatocellular carcinoma
  Status epilepticus seizure
  D-2-hydroxyglutaric aciduria
  Adult glioblastoma
  2-hydroxyglutaric aciduria
  Acute monocytic leukemia
  Anaplastic astrocytoma
  Brain neoplasm
  Chondrosarcoma
  D-2-hydroxyglutaric aciduria 1
  Hemangioma
  Leukemia
  Myelodysplastic syndrome
  Osteoarthritis
• UniProt ID: IDHP_HUMAN
• PDB ID: 4JA8; 5GIS; 5I95; 5I96; 5SVN; 5SVO; 6ADI; 6UJ7; 6UJ8; 6UJ9; 6VFZ
• EC Number: 1.1.1.42
• Pfam ID: PF00180
• 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.
• KEGG Pathway:
  Citrate cycle (TCA cycle) (hsa00020)
  Glutathione metabolism (hsa00480)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  2-Oxocarboxylic acid metabolism (hsa01210)
  Biosynthesis of amino acids (hsa01230)
  Peroxisome (hsa04146)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Citric acid cycle (TCA cycle) (R-HSA-71403)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
• BioCyc Pathway: MetaCyc:HS00021-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal dominant	[1]
Angioimmunoblastic T-cell Lymphoma	DISZPFTL	Strong	Genetic Variation	[2]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[3]
Cholangiocarcinoma	DIS71F6X	Strong	Genetic Variation	[4]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[5]
D-2-hydroxyglutaric aciduria 2	DISWXIE7	Strong	Autosomal dominant	[6]
Glioma susceptibility 1	DISD5L1R	Strong	Genetic Variation	[7]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[5]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[8]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[9]
Kidney failure	DISOVQ9P	Strong	Biomarker	[8]
Malignant glioma	DISFXKOV	Strong	Genetic Variation	[10]
Melanoma	DIS1RRCY	Strong	Biomarker	[11]
Osteoporosis	DISF2JE0	Strong	Biomarker	[12]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[13]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Strong	Genetic Variation	[14]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[15]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[16]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[17]
Status epilepticus seizure	DISY3BIC	moderate	Biomarker	[18]
D-2-hydroxyglutaric aciduria	DIS3JMXH	Supportive	Autosomal dominant	[6]
Adult glioblastoma	DISVP4LU	Disputed	Biomarker	[19]
2-hydroxyglutaric aciduria	DIS4P821	Limited	Biomarker	[8]
Acute monocytic leukemia	DIS28NEL	Limited	Biomarker	[20]
Anaplastic astrocytoma	DISSBE0K	Limited	Genetic Variation	[21]
Brain neoplasm	DISY3EKS	Limited	Genetic Variation	[22]
Chondrosarcoma	DIS4I7JB	Limited	Genetic Variation	[23]
D-2-hydroxyglutaric aciduria 1	DISFYZD5	Limited	Genetic Variation	[24]
Hemangioma	DISDCGAG	Limited	Genetic Variation	[25]
Leukemia	DISNAKFL	Limited	Genetic Variation	[26]
Myelodysplastic syndrome	DISYHNUI	Limited	Biomarker	[27]
Osteoarthritis	DIS05URM	Limited	Biomarker	[28]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Isocitrate dehydrogenase , mitochondrial (IDH2) affects the response to substance of Vinblastine.	[52]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Isocitrate dehydrogenase , mitochondrial (IDH2).	[29]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Isocitrate dehydrogenase , mitochondrial (IDH2).	[37]

21 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[31]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[33]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[34]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[35]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[36]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[38]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[39]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[40]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[41]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[42]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[43]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[44]
SNS-595	DMZE2JO	Phase 3	SNS-595 increases the activity of Isocitrate dehydrogenase , mitochondrial (IDH2).	[45]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[46]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[48]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the activity of Isocitrate dehydrogenase , mitochondrial (IDH2).	[49]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[50]
SAG	DMHOG7W	Investigative	SAG increases the expression of Isocitrate dehydrogenase , mitochondrial (IDH2).	[51]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] The pathological features of angioimmunoblastic T-cell lymphomas with IDH2(R172) mutations.Mod Pathol. 2019 Jul;32(8):1123-1134. doi: 10.1038/s41379-019-0254-4. Epub 2019 Apr 5.
• [3] D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice.Genes Dev. 2014 Mar 1;28(5):479-90. doi: 10.1101/gad.231233.113.
• [4] Targeting cholangiocarcinoma.Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864(4 Pt B):1454-1460. doi: 10.1016/j.bbadis.2017.08.027. Epub 2017 Aug 24.
• [5] Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Nat Biotechnol. 2016 Feb;34(2):155-63. doi: 10.1038/nbt.3391. Epub 2015 Nov 30.
• [6] IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science. 2010 Oct 15;330(6002):336. doi: 10.1126/science.1192632. Epub 2010 Sep 16.
• [7] IDH2 mutation in gliomas including novel mutation.Neuropathology. 2015 Jun;35(3):236-44. doi: 10.1111/neup.12187. Epub 2014 Dec 12.
• [8] A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D-2-hydroxyglutaric aciduria type II mouse model.J Inherit Metab Dis. 2016 Nov;39(6):807-820. doi: 10.1007/s10545-016-9960-y. Epub 2016 Jul 28.
• [9] Integrative Analysis Defines Distinct Prognostic Subgroups of Intrahepatic Cholangiocarcinoma.Hepatology. 2019 May;69(5):2091-2106. doi: 10.1002/hep.30493. Epub 2019 Feb 28.
• [10] Comparison of (18)F-GE-180 and dynamic (18)F-FET PET in high grade glioma: a double-tracer pilot study.Eur J Nucl Med Mol Imaging. 2019 Mar;46(3):580-590. doi: 10.1007/s00259-018-4166-1. Epub 2018 Sep 22.
• [11] Oxalomalate reduces tumor progression in melanoma via ROS-dependent proapoptotic and antiangiogenic effects.Biochimie. 2019 Mar;158:165-171. doi: 10.1016/j.biochi.2019.01.004. Epub 2019 Jan 9.
• [12] Proteomic analysis of circulating monocytes in Chinese premenopausal females with extremely discordant bone mineral density.Proteomics. 2008 Oct;8(20):4259-72. doi: 10.1002/pmic.200700480.
• [13] IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies.Blood. 2019 Jan 10;133(2):156-167. doi: 10.1182/blood-2018-05-850826. Epub 2018 Nov 19.
• [14] RHOA G17V mutation in angioimmunoblastic T-cell lymphoma: A potential biomarker for cytological assessment.Exp Mol Pathol. 2019 Oct;110:104294. doi: 10.1016/j.yexmp.2019.104294. Epub 2019 Aug 5.
• [15] Mutations of Epigenetic Modifier Genes as a Poor Prognostic Factor in Acute Promyelocytic Leukemia Under Treatment With All-Trans Retinoic Acid and Arsenic Trioxide.EBioMedicine. 2015 Apr 12;2(6):563-71. doi: 10.1016/j.ebiom.2015.04.006. eCollection 2015 Jun.
• [16] 2-Hydroxyglutarate in Cancer Cells.Antioxid Redox Signal. 2020 Nov 1;33(13):903-926. doi: 10.1089/ars.2019.7902. Epub 2020 Jan 22.
• [17] Isocitrate dehydrogenase 2 inhibits gastric cancer cell invasion via matrix metalloproteinase 7.Tumour Biol. 2016 Apr;37(4):5225-30. doi: 10.1007/s13277-015-4358-2. Epub 2015 Nov 10.
• [18] Altered mitochondrial acetylation profiles in a kainic acid model of temporal lobe epilepsy.Free Radic Biol Med. 2018 Aug 1;123:116-124. doi: 10.1016/j.freeradbiomed.2018.05.063. Epub 2018 May 17.
• [19] Cancer genetic markers according to radiotherapeutic response in patients with primary glioblastoma - Radiogenomic approach for precision medicine.Radiother Oncol. 2019 Feb;131:66-74. doi: 10.1016/j.radonc.2018.11.025. Epub 2018 Dec 31.
• [20] Detection Of Mutations In The Isocitrate Dehydrogenase Genes (IDH1/IDH2) Using castPCR(TM) In Patients With AML And Their Clinical Impact In Mexico City.Onco Targets Ther. 2019 Oct 1;12:8023-8031. doi: 10.2147/OTT.S219703. eCollection 2019.
• [21] c-Met Expression Is a Useful Marker for Prognosis Prediction in IDH-Mutant Lower-Grade Gliomas and IDH-Wildtype Glioblastomas.World Neurosurg. 2019 Jun;126:e1042-e1049. doi: 10.1016/j.wneu.2019.03.040. Epub 2019 Mar 13.
• [22] Rapid detection of 2-hydroxyglutarate in frozen sections of IDH mutant tumors by MALDI-TOF mass spectrometry.Acta Neuropathol Commun. 2018 Mar 2;6(1):21. doi: 10.1186/s40478-018-0523-3.
• [23] IDH mutation status in a series of 88 head and neck chondrosarcomas: different profile between tumors of the skull base and tumors involving the facial skeleton and the laryngotracheal tract.Hum Pathol. 2019 Feb;84:183-191. doi: 10.1016/j.humpath.2018.09.015. Epub 2018 Oct 5.
• [24] A lymphoblast model for IDH2 gain-of-function activity in d-2-hydroxyglutaric aciduria type II: novel avenues for biochemical and therapeutic studies.Biochim Biophys Acta. 2011 Nov;1812(11):1380-4. doi: 10.1016/j.bbadis.2011.08.006. Epub 2011 Aug 24.
• [25] Constitutional abnormalities of IDH1 combined with secondary mutations predispose a patient with Maffucci syndrome to acute lymphoblastic leukemia.Pediatr Blood Cancer. 2017 Dec;64(12). doi: 10.1002/pbc.26647. Epub 2017 May 24.
• [26] The Evolving Landscape in the Development of Isocitrate Dehydrogenase Mutant Inhibitors.Mini Rev Med Chem. 2016;16(16):1344-1358. doi: 10.2174/1389557516666160609085520.
• [27] Isocitrate dehydrogenase 2 mutations correlate with leukemic transformation and are predicted by 2-hydroxyglutarate in myelodysplastic syndromes.J Cancer Res Clin Oncol. 2018 Jun;144(6):1037-1047. doi: 10.1007/s00432-018-2627-3. Epub 2018 Mar 16.
• [28] Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: a decrease in mitochondrial superoxide dismutase points to a redox imbalance.Mol Cell Proteomics. 2009 Jan;8(1):172-89. doi: 10.1074/mcp.M800292-MCP200. Epub 2008 Sep 9.
• [29] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [30] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [31] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [32] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [33] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [34] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [35] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [36] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [37] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [38] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [39] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [40] SIRT3 Mediates the Antioxidant Effect of Hydrogen Sulfide in Endothelial Cells. Antioxid Redox Signal. 2016 Feb 20;24(6):329-43. doi: 10.1089/ars.2015.6331. Epub 2015 Nov 10.
• [41] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [42] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [43] Novel roles of folic acid as redox regulator: Modulation of reactive oxygen species sinker protein expression and maintenance of mitochondrial redox homeostasis on hepatocellular carcinoma. Tumour Biol. 2017 Jun;39(6):1010428317702649. doi: 10.1177/1010428317702649.
• [44] Effects of paclitaxel on proliferation and apoptosis in human acute myeloid leukemia HL-60 cells. Acta Pharmacol Sin. 2004 Mar;25(3):378-84.
• [45] Vosaroxin induces mitochondrial dysfunction and apoptosis in cervical cancer HeLa cells: Involvement of AMPK/Sirt3/HIF-1 pathway. Chem Biol Interact. 2018 Jun 25;290:57-63. doi: 10.1016/j.cbi.2018.05.011. Epub 2018 May 22.
• [46] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [47] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [48] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [49] Effect of soluble nickel on cellular energy metabolism in A549 cells. Exp Biol Med (Maywood). 2006 Oct;231(9):1474-80. doi: 10.1177/153537020623100905.
• [50] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [51] Differential role of Pax6 and its interaction with Shh-Gli1-IDH2 axis in regulation of glioma growth and chemoresistance. J Biochem Mol Toxicol. 2023 Feb;37(2):e23241. doi: 10.1002/jbt.23241. Epub 2022 Oct 7.
• [52] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.