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isocitrate dehydrogenase (NADP(+)) 1

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Target not currently curated in GtoImmuPdb

Target id: 2884

Nomenclature: isocitrate dehydrogenase (NADP(+)) 1

Systematic Nomenclature: IDH1

Family: 1.1.1.42 Isocitrate dehydrogenases, Citrate metabolism

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 414 2q34 IDH1 isocitrate dehydrogenase (NADP(+)) 1
Mouse - 414 1 32.91 cM Idh1 isocitrate dehydrogenase 1 (NADP+), soluble
Rat - 414 9q32 Idh1 isocitrate dehydrogenase (NADP(+)) 1
Previous and Unofficial Names Click here for help
isocitrate dehydrogenase 1 (NADP) | isocitrate dehydrogenase 1 (NADP+) | isocitrate dehydrogenase 1 (NADP+), soluble | isocitrate dehydrogenase (NADP(+)) 1, cytosolic | isocitrate dehydrogenase [NADP] cytoplasmic
Database Links Click here for help
Alphafold O75874 (Hs), O88844 (Mm), P41562 (Rn)
BRENDA 1.1.1.42
ChEMBL Target CHEMBL2007625 (Hs)
Ensembl Gene ENSG00000138413 (Hs), ENSMUSG00000025950 (Mm), ENSRNOG00000015020 (Rn)
Entrez Gene 3417 (Hs), 15926 (Mm), 24479 (Rn)
Human Protein Atlas ENSG00000138413 (Hs)
KEGG Enzyme 1.1.1.42
KEGG Gene hsa:3417 (Hs), mmu:15926 (Mm), rno:24479 (Rn)
OMIM 147700 (Hs)
Pharos O75874 (Hs)
RefSeq Nucleotide NM_005896 (Hs), NM_001111320 (Mm), NM_031510 (Rn)
RefSeq Protein NP_005887 (Hs), NP_001104790 (Mm), NP_113698 (Rn)
UniProtKB O75874 (Hs), O88844 (Mm), P41562 (Rn)
Wikipedia IDH1 (Hs)
Enzyme Reaction Click here for help
EC Number: 1.1.1.42 Isocitrate + NADP(+) <=> 2-oxoglutarate + CO2 + NADPH
Description Reaction Reference
Isocitrate + NADP+ <=> 2-oxoglutarate + CO2 + NADPH

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
AGI-5198 Small molecule or natural product Primary target of this compound Hs Inhibition 4.9 pKi
⤷ pKi 4.9 (Ki 1.3x10-5 M)
LY3410738 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.0 – 8.2 pIC50 1
⤷ pIC50 8.2 (IC50 6.27x10-9 M) [1]
Description: Inhibition of hIDH1 with R132H mutation
pIC50 7.0 (IC50 1.05x10-7 M) [1]
Description: Inhibition of WT hIDH1
safusidenib Small molecule or natural product Ligand has a PDB structure Hs Inhibition 6.9 pIC50 8
⤷ pIC50 6.9 (IC50 1.3x10-7 M) [8]
Description: Inhibition of hIDH1R132C
olutasidenib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibition 6.0 – 7.0 pIC50 5
⤷ pIC50 6.0 – 7.0 (IC50 1x10-6 – 1x10-7 M) [5]
Description: Inhibition of mutant IDH1 R132H and R132C in an enzymatic assay measuring inhibition of 2-HG production.
ivosidenib Small molecule or natural product Approved drug Primary target of this compound Hs Inhibition - - 4
⤷ [4]
vorasidenib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition - - 3
⤷ [3]
Description: Inhibits mutant IDH1.
Inhibitor Comments
Ivosidenib, olutasidenib and vorasidenib are highly selective for mutant IDH isoforms and have low activity against wild type enzyme.
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Cellular signalling
Immuno Disease Associations
Disease Name:  Acute myeloid leukemia
Disease Synonyms:  no synonynms
Comment:  Mutant IDH1 isoforms are found in 6 to 10% of cases of AML and in a variety of solid tumours, and make these tumours susceptible to IDH1 inhibitor therapy.
Disease X-refs:  Disease Ontology: DOID:9119
OMIM: 601626
Orphanet: ORPHA519
References:  2,6-7,9,11,13
Clinically-Relevant Mutations and Pathophysiology Click here for help
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human R132C, R132G, R132S, R132H, R132L 394C>T, 394C>G, 394C>A, 395G>A, 395G>T IDH1 mutations associated with cancers such as glioma and some hematological malignancies. 10,12
Clinically-Relevant Mutations and Pathophysiology Comments
The majority (80-90%) of IDH1 mutations in glioma are R132H. IDH1 is mutated in the majority of lower grade diffuse gliomas (grades II-III) and also in most secondary glioblastomas. It is rare in newly diagnosed glioblastoma.

References

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1. Bauer RA, Boulet EL, Burkholder TP, Hahn PJ, Rankovic Z. (2021) 7-phenylethylamino-4H-pyrimido[4,5-d][1,3]oxazin-2-one compounds as mutant IDH1 and IDH2 inhibitors. Patent number: US11001596B2. Assignee: Eli Lilly and Co. Priority date: 08/12/2007. Publication date: 11/05/2021.

2. DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA et al.. (2018) Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med, 378 (25): 2386-2398. [PMID:29860938]

3. Konteatis Z, Artin E, Nicolay B, Straley K, Padyana AK, Jin L, Chen Y, Narayaraswamy R, Tong S, Wang F et al.. (2020) Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma. ACS Med Chem Lett, 11 (2): 101-107. DOI: 10.1021/acsmedchemlett.9b00509 [PMID:32071674]

4. Lemieux RM, Popovici-Muller J, Travins J, Cai Z, Cui D, Zhou D. (2013) Therapeutically active compounds and their methods of use. Patent number: WO2013107291. Assignee: Agios Pharmaceuticals, Inc.. Priority date: 19/01/2012. Publication date: 25/07/2013.

5. Lin J, Ericsson A, Campbell A-M, Gustafson G, Wang Z, Diebold RB, Ashwell S, Lancia DR Jr, Caravella A, Lu W. (2017) Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors. Patent number: US9834539B2. Assignee: Forma Tm2 Inc. Priority date: 19/09/2014. Publication date: 05/12/2017.

6. Linos K, Tafe LJ. (2018) Isocitrate dehydrogenase 1 mutations in melanoma frequently co-occur with NRAS mutations. Histopathology, 73 (6): 963-968. [PMID:30003571]

7. Ma T, Zou F, Pusch S, Xu Y, von Deimling A, Zha X. (2018) Inhibitors of Mutant Isocitrate Dehydrogenases 1 and 2 (mIDH1/2): An Update and Perspective. J Med Chem, 61 (20): 8981-9003. [PMID:29847930]

8. Machida Y, Nakagawa M, Matsunaga H, Yamaguchi M, Ogawara Y, Shima Y, Yamagata K, Katsumoto T, Hattori A, Itoh M et al.. (2020) A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model. Mol Cancer Ther, 19 (2): 375-383. [PMID:31727689]

9. Morizane C, Ueno M, Ikeda M, Okusaka T, Ishii H, Furuse J. (2018) New developments in systemic therapy for advanced biliary tract cancer. Jpn J Clin Oncol, 48 (8): 703-711. [PMID:29893894]

10. Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E et al.. (2013) An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science, 340 (6132): 626-30. [PMID:23558169]

11. Sidaway P. (2018) Ivosidenib effective in IDH1-mutant AML. Nat Rev Clin Oncol, 15 (8): 472. [PMID:29925981]

12. Walter MJ, Shen D, Shao J, Ding L, White BS, Kandoth C, Miller CA, Niu B, McLellan MD, Dees ND et al.. (2013) Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. Leukemia, 27 (6): 1275-82. [PMID:23443460]

13. Zhao Q, Manning JR, Sutton J, Costales A, Sendzik M, Shafer CM, Levell JR, Liu G, Caferro T, Cho YS et al.. (2018) Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Orally Bioavailable and Brain Penetrant Mutant IDH1 Inhibitors. ACS Med Chem Lett, 9 (7): 746-751. [PMID:30034612]

How to cite this page

1.1.1.42 Isocitrate dehydrogenases: isocitrate dehydrogenase (NADP(+)) 1. Last modified on 04/08/2023. Accessed on 23/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2884.