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Identification of a new selective chemical inhibitor of mutant isocitrate dehydrogenase-1.

ABSTRACT: BACKGROUND:Recent genome-wide sequencing studies have identified unexpected genetic alterations in cancer. In particular, missense mutations in isocitrate dehydrogenase-1 (IDH1) at arginine 132, mostly substituted into histidine (IDH1-R132H) were observed to frequently occur in glioma patients. METHODS:We have purified recombinant IDH1 and IDH1-R132H proteins and monitored their catalytic activities. In parallel experiments, we have attempted to find new selective IDH1-R132H chemical inhibitor(s) from a fragment-based chemical library. RESULTS:We have found that IDH1, but not IDH1-R132H, can catalyze the conversion of isocitrate into ?-ketoglutarate (?-KG). In addition, we have observed that IDH1-R132H was more efficient than IDH1 in converting ?-KG into (R)-2-hydroxyglutarate (R-2HG). Moreover, we have identified a new hit molecule, e.g., 2-(3-trifluoromethylphenyl)isothioazol-3(2H)-one as a new selective IDH1-R132H inhibitor. CONCLUSIONS:We have observed an underlying biochemical mechanism explaining how a heterozygous IDH1 mutation contributes to the generation of R-2HG and increases cellular histone H3 trimethylation levels. We have also identified a novel selective IDH1-R132H chemical hit molecule, e.g., 2-(3-trifluoromethylphenyl)isothioazol-3(2H)-one, which could be used for a future lead development against IDH1-R132H.

SUBMITTER: Kim HJ

PROVIDER: S-EPMC4384718 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Identification of a new selective chemical inhibitor of mutant isocitrate dehydrogenase-1.

Kim Hyo-Joon HJ Choi Bu Young BY Keum Young-Sam YS

Journal of cancer prevention 20150301 1

<h4>Background</h4>Recent genome-wide sequencing studies have identified unexpected genetic alterations in cancer. In particular, missense mutations in isocitrate dehydrogenase-1 (IDH1) at arginine 132, mostly substituted into histidine (IDH1-R132H) were observed to frequently occur in glioma patients.<h4>Methods</h4>We have purified recombinant IDH1 and IDH1-R132H proteins and monitored their catalytic activities. In parallel experiments, we have attempted to find new selective IDH1-R132H chemi ...[more]

PMID: 25853107

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Project description:ImportanceEnasidenib mesylate, a mutant isocitrate dehydrogenase 2 (IDH2) protein inhibitor that promotes differentiation of leukemic myeloblasts, was recently approved by the US Food and Drug Administration for use in relapsed/refractory (R/R) mutant IDH2 acute myeloid leukemia (AML). During the first study of enasidenib in humans, a minority of patients with advanced myeloid neoplasms experienced unexpected signs/symptoms of a differentiation syndrome (DS), a potentially lethal entity.ObjectiveTo characterize IDH-inhibitor-associated DS (IDH-DS) and its effective management.Design, setting, and participantsUsing data obtained from a multicenter, open-label, pivotal phase 1/2 study of enasidenib, a differentiation syndrome review committee retrospectively evaluated potential cases of IDH-DS in enasidenib-treated patients with R/R AML. Data were collected between August 27, 2013, and October 14, 2016. The committee identified and agreed on signs and symptoms characteristic of IDH-DS and developed an algorithm for identification and treatment. Among 281 patients with R/R AML enrolled in the trial, the committee identified 72 patients for review based on investigator-reported cases of DS (n = 33) or reported adverse events or signs and symptoms characteristic of IDH-DS.InterventionsTreatment with enasidenib at a dosage of 50 to 650 mg/d was evaluated during the dose-escalation phase, and a dosage of 100 mg/d was used in the phase 1 expansion and phase 2, all in continual 28-day cycles.Main outcomes and measuresUnexpected adverse events of IDH-DS during the phase 1/2 study.ResultsThirty-three of the 281 patients (11.7%) were identified as having possible or probable IDH-DS. Median age of those 33 patients was 70 years (range, 38-80 years); 20 (60.6%) were male. The most frequent manifestations were dyspnea, fever, pulmonary infiltrates, and hypoxia. Median time to onset was 30 days (range, 7-129 days). Patients who experienced IDH-DS were less likely to have less than 20% bone marrow blasts (6% vs 22%, P = .04) and more likely to have undergone fewer previous anticancer regimens (median, 1.0 [range, 1-4] vs 2.0 [range, 1-14], P = .05) at study entry than those who did not. Thirteen patients (39.4%) had concomitant leukocytosis. Isocitrate dehydrogenase differentiation syndrome was effectively managed with systemic corticosteroids. The enasidenib regimen was interrupted for 15 patients (45.5%), but permanent discontinuation of treatment was not required.Conclusions and relevanceIsocitrate dehydrogenase differentiation syndrome is a recognizable and potentially lethal clinical entity, occurring in approximately 12% of enasidenib-treated patients with mutant-IDH2 R/R AML. It requires prompt recognition and management. As use of mutant IDH inhibitors increases, these findings and recommendations are increasingly germane to care of patients with mutant-IDH neoplasms.Trial registrationclinicaltrials.gov Identifier: NCT01915498.

Project description:PurposeIvosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (mIDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition-related differentiation and apoptosis.Patients and methodsThis was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed mIDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922).ResultsTwenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). mIDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission.ConclusionIvosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving mIDH1 mutation clearance.

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Identification of a new selective chemical inhibitor of mutant isocitrate dehydrogenase-1.

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Identification of a new selective chemical inhibitor of mutant isocitrate dehydrogenase-1.

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