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 clinical response in AML patients. Hence, enasidenib and ivosidenib, the IDH2 and IDH1 inhibitors developed by Agios Pharmaceuticals, have been approved by the Food and Drug Administration on 1 August 2017 and 20 July 2018 for the treatment of adult relapsed or refractory (R/R) AML with IDH2 and IDH1 mutations, respectively. IDH inhibitor monotherapy for R/R AML is efficacious and safe; however, there are problems, such as primary or acquired resistance. Clinical trials of IDH inhibitors combined with hypomethylating agents or standard chemotherapy for the treatment of R/R AML or newly diagnosed AML, as well as in post hematopoietic stem cell transplantation as maintenance therapy, are ongoing. This article summarizes the use of IDH inhibitors in AML with IDH mutations.

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

“…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].…”

“…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].…”

Standardization of sampling and sample preparation for analysis of human monocyte subsets in peripheral blood

“…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].…”

The Landscape of the Anti-Kinase Activity of the IDH1 Inhibitors

“…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].…”