2019
DOI: 10.1186/s40364-019-0173-z
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Isocitrate dehydrogenase inhibitors in acute myeloid leukemia

Abstract: Isocitrate dehydrogenase (IDH) is a key enzyme involved in the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle. IDH mutation produces a neomorphic enzyme, which can lead to the abnormal accumulation of R-2-HG and promotes leukemogenesis. IDH mutation occurs in 20% of acute myeloid leukemia (AML) patients, mainly including IDH1 R132, IDH2 R140, and IDH2 R172. Different mutant isoforms have different prognostic values. In recent years, IDH inhibitors have shown good clini… Show more

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Cited by 83 publications
(64 citation statements)
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References 89 publications
(87 reference statements)
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“…The result of these mutations is a neomorphic activity of the enzyme that causes the formation of D-2-hydroxyglutarate (2-HG), a metabolite with oncogenic properties [22]. Its accumulation inhibits various α-KG-dependent dioxygenases involved in epigenetic regulation, including those responsible for histones and DNA demethylation, such as TET1/2 methylcytosine hydroxylases (Table 2, Figure 2) [23][24][25]. Consistently, TET2 inactivation is mutually exclusive with IDH1 and IDH2 mutations [26].…”
Section: Idh1 and Idh2 Mutationsmentioning
confidence: 90%
See 1 more Smart Citation
“…The result of these mutations is a neomorphic activity of the enzyme that causes the formation of D-2-hydroxyglutarate (2-HG), a metabolite with oncogenic properties [22]. Its accumulation inhibits various α-KG-dependent dioxygenases involved in epigenetic regulation, including those responsible for histones and DNA demethylation, such as TET1/2 methylcytosine hydroxylases (Table 2, Figure 2) [23][24][25]. Consistently, TET2 inactivation is mutually exclusive with IDH1 and IDH2 mutations [26].…”
Section: Idh1 and Idh2 Mutationsmentioning
confidence: 90%
“…On the other hand, some studies suggest that IDH1 and IDH2 mutations could contribute to progression from MDS or MPN to AML, through a mechanism of reactive oxygen species (ROS) accumulation and DNA damage leading to stabilization and activation of HIF-1 [29][30][31]. Recently, the Food and Drug Administration (FDA) approved IDH1 and IDH2 inhibitors ivosidenib and enasidenib for the treatment of adult relapsed or refractory AML with IDH1 and IDH2 mutations [25].…”
Section: Idh1 and Idh2 Mutationsmentioning
confidence: 99%
“…Third, CPX-351 is encapsulated in nanoscale liposomes of cytarabine and daunorubicin at a synergistic 5:1 molar ratio; this agent may become useful even for high-risk patients and may also be used in elderly patients [362,363]. Finally, inhibitors of mutated IDH are also used in the treatment of this patient subset [364].…”
Section: The Diagnosis Of Amlmentioning
confidence: 99%
“…Although it is sometimes described as being R132H selective, it is rather slow binding and non-competitive to the substrate (NADPH) inhibitor of the wild-type IDH1 with activity slightly lower than in the mutant (IC 50 = 24 vs. 12 nM according to the report [20]). A series of other compounds such as olutasidenib, IDH305 or GSK-321 (see Figure 2) are currently under investigation [21]. The last two are selective inhibitors against the IDH1 mutants, which they bind to an allosteric pocket in order to stabilize an enzyme in a catalytically inactive conformation [22,23].…”
Section: Introductionmentioning
confidence: 99%