Isocitrate Dehydrogenase (IDH)

Isocitrate dehydrogenase (IDH) is an important enzyme in the tricarboxylic acid cycle, which occurs in the mitochondrial matrix. IDH is responsible for catalyzing the reversible conversion of isocitrate to alpha-ketoglutarate and CO2 in a two-step reaction. The first step of the reaction involves the oxidation of isocitrate to the intermediate oxalosuccinate. The second step of the reaction looses the beta-carboxylate of the oxalosuccinate intermediate as carbon dioxide leaving alpha-ketogluterate. During the catalyzation of isocitrate to alpha ketoglutarate either NADH or NADPH is produced along with carbon dioxide.

1355326-21-4
Mutant IDH1-IN-1
1355326-21-4
1355326-35-0
AGI-5198
1355326-35-0
1429176-69-1
Mutant IDH1-IN-2
1429176-69-1
1429180-08-4
SCHEMBL14831541
1429180-08-4
1432660-47-3
AGI-6780
1432660-47-3
B0084-470859
Enasidenib
1446502-11-9
1448347-49-6
Ivosidenib
1448347-49-6
Enasidenib mesylate
1650550-25-6
1816331-63-1
GSK321
1816331-63-1
GSK864
1816331-66-4
TC-E 5008
50405-58-8
alpha-Mangostin
6147-11-1

Background


An overview of IDH

Isocitrate dehydrogenase (IDH) is a critical enzyme involved in the tricarboxylic acid cycle, catalyzing the conversion of isocitrate to α-ketoglutarate (αKG), which is rate-limit process in the Krebs cycle. IDH mutation in somatic cells will lead to the loss of this function, and convertsαKG into tumor metabolite D-2-hydroxpentanoic acid resulting DNA or histone hypermethylation.

Major types of IDH

There are three members in the family of IDHs : IDH1, IDH2 and IDH3, and all of them are able to catalyze the oxidative decarboxylation of isocitrate to produceαKG and CO2. Mg2+ or Mn2+ and the cofactors NADP+ or NAD+ are the electron acceptors in these processes, and generate NADPH or NADH. The structures of IDH1 and IDH2 are similar, belonging to the NADP+-dependent family with different subcellular localization of the two proteins. IDH3, mitochondrial isoforms of IDH, is composed of three types of subunits: IDH3A, IDH3B, IDH3G.

Inhibition of IDH

According to the target, IDH inhibitors can be divided into three categories: IDH1 inhibitors, IDH2 inhibitors and IDH1 /IDH2 inhibitors. The first IDH1 inhibitor AGI-5918 and IDH2 inhibitor AGI-6780 were discovered by Agios. Later on, Agios developed new drugs for the continued perfection of IDH inhibitors, like AG-120, AG-221 and AG-881, and all of them are in clinical use. Other pharmaceutical companies have also developed many inhibitors targeting IDH, such as GSK 321 by GlaxoSmithKline, BAY-1436032 by Bayer, IDH305 by Novartis and FT-2012 by Forma Therapeutics.

IDH and diseases

IDH mutation can be discovered in many diseases, such as low-grade glioma, secondary malignant glioma, melanoma, angioimmunoblastic T-cell lymphoma, myeloproliferative neoplasms, myelodysplastic syndrome and acute myelocytic leukemia. The discovery of somatic mutation in the IDH enzymes is of great significance in cancer biology, making IDH a rational target for the treatment of cancer.

References:

1. Wang, H. Y., Ye, Z. & Liu, X. K. Research progress of isocitrate dehydrogenase inhibitors. Chinese Journal of New Drugs 26, 1272-1278 (2017).

2. Yen, K. E., Bittinger, M. A., Su, S. M. & Fantin, V. R. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene 29, 6409 (2010).

3. Medeiros, B. C. et al. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia 31, 272-281 (2017).