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Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants.

ABSTRACT: Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases. Most tumor-relevant IDH1 mutations are deficient in the normal oxidization of isocitrate to ?-ketoglutarate (?KG), but gain the neomorphic activity of reducing ?KG to D-2-hydroxyglutarate (D2HG), which drives tumorigenesis. We found previously that IDH1 mutants exhibit one of two reactivities: deficient ?KG and moderate D2HG production (including commonly observed R132H and R132C) or moderate ?KG and high D2HG production (R132Q). Here, we identify a third type of reactivity, deficient ?KG and high D2HG production (R132L). We show that R132Q IDH1 has unique structural features and distinct reactivities towards mutant IDH1 inhibitors. Biochemical and cell-based assays demonstrate that while most tumor-relevant mutations were effectively inhibited by mutant IDH1 inhibitors, R132Q IDH1 had up to a 16?300-fold increase in IC50 versus R132H IDH1. Only compounds that inhibited wild-type (WT) IDH1 were effective against R132Q. This suggests that patients with a R132Q mutation may have a poor response to mutant IDH1 therapies. Molecular dynamics simulations revealed that near the NADP+/NADPH-binding site in R132Q IDH1, a pair of ?-helices switches between conformations that are more wild-type-like or more mutant-like, highlighting mechanisms for preserved WT activity. Dihedral angle changes in the dimer interface and buried surface area charges highlight possible mechanisms for loss of inhibitor affinity against R132Q. This work provides a platform for predicting a patient's therapeutic response and identifies a potential resistance mutation that may arise upon treatment with mutant IDH inhibitors.

SUBMITTER: Avellaneda Matteo D

PROVIDER: S-EPMC6422176 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants.

Avellaneda Matteo Diego D Wells Grace A GA Luna Lucas A LA Grunseth Adam J AJ Zagnitko Olga O Scott David A DA Hoang An A Luthra Amit A Swairjo Manal A MA Schiffer Jamie M JM Sohl Christal D CD

The Biochemical journal 20181022 20

Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases. Most tumor-relevant IDH1 mutations are deficient in the normal oxidization of isocitrate to α-ketoglutarate (αKG), but gain the neomorphic activity of reducing αKG to D-2-hydroxyglutarate (D2HG), which drives tumorigenesis. We found previously that IDH1 mutants exhibit one of two reactivities: deficient αKG and moderate D2HG production ...[more]

PMID: 30249606

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Project description:The European Commission has recently proposed draft criteria for the identification of endocrine disrupting chemicals (EDCs) that pose a significant hazard to humans or the environment. Identifying and characterizing toxic hazards based on the manner by which adverse effects are produced rather than on the nature of those adverse effects departs from traditional practice and requires a proper interpretation of the evidence regarding the chemical's ability to produce physiological effect(s) via a specific mode of action (MoA). The ability of any chemical to produce a physiological effect depends on its pharmacokinetics and the potency by which it acts via the various MoAs that can lead to the particular effect. A chemical's potency for a specific MoA-its mechanistic potency-is determined by two properties: (1) its affinity for the functional components that comprise the MoA, i.e., its specific receptors, enzymes, transporters, transcriptional elements, etc., and (2) its ability to alter the functional state of those components (activity). Using the agonist MoA via estrogen receptor alpha, we illustrate an empirical method for determining a human-relevant potency threshold (HRPT), defined as the minimum level of mechanistic potency necessary for a chemical to be able to act via a particular MoA in humans. One important use for an HRPT is to distinguish between chemicals that may be capable of, versus those likely to be incapable of, producing adverse effects in humans via the specified MoA. The method involves comparing chemicals that have different ER? agonist potencies with the ability of those chemicals to produce ER?-mediated agonist responses in human clinical trials. Based on this approach, we propose an HRPT for ER? agonism of 1E-04 relative to the potency of the endogenous estrogenic hormone 17?-estradiol or the pharmaceutical estrogen, 17?-ethinylestradiol. This approach provides a practical way to address Hazard Identification according to the draft criteria for identification of EDCs recently proposed by the European Commission.

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Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants.

Publications

Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants.

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