Assessing inhibitors of mutant isocitrate dehydrogenase using a suite of pre-clinical discovery assays

Urban, Daniel J.; Martínez, Natàlia; Davis, Mindy I.; Brimacombe, Kyle R.; Cheff, Dorian M.; Lee, Tobie D.; Henderson, Mark J.; Titus, Steven A.; Pragani, Rajan; Rohde, Jason M.; Liu, Li; Fang, Yuhong; Surendra, Karavadhi; Shah, Pranav; Lee, Olivia W.; Wang, Amy; McIver, Andrew L.; Zheng, Hongchao; Wang, Xiaodong; Xu, Xin; Jadhav, Ajit; Simeonov, Anton; Shen, Min; Boxer, Matthew B.; Hall, Matthew D.

doi:10.1038/s41598-017-12630-x

Cited by 60 publications

(64 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Preliminary trials indicate the selective inhibitory strength of AG-120 and AG-221 compounds in IDH1 and IDH2 mutant enzymes, respectively, by inhibiting mutant IDH activity and 2-HG accumulation, an oncometabolite [99,100]. AG-120 and another mutant IDH inhibitor, Novartis-530, were found to be the most biochemically potent inhibitors among all nine inhibitors tested in a comparative study [101]. In the same study, both proved to cause the highest reduction of 2-HG levels in six different cancer cell lines with IDH mutation (HT1080 fibrosarcoma, SNU1079, and RBE cholangiocarcinoma, JJ012 chondrosarcoma, U87 glioblastoma, and THP-1 AML).…”

Section: Inhibitors and Drugsmentioning

confidence: 96%

“…Meanwhile, in preliminary phase I clinical trials in patients with advanced hematologic malignancies, the objective response rate ranged from 31% to 40%, with durable responses (>1 year) observed [102]. In addition, AG-881, a brain-penetrant dual IDH1/2 mutant inhibitor, is currently in phase I trial against solid tumors [101]. Inhibition of LDH-A, which facilitates pyruvate conversion to lactate, diminished MYC-driven tumors in xenograft models.…”

Section: Inhibitors and Drugsmentioning

confidence: 99%

See 1 more Smart Citation

Rescue of TCA Cycle Dysfunction for Cancer Therapy

Marquez

Flores

et al. 2019

JCM

View full text Add to dashboard Cite

Mitochondrion, a maternally hereditary, subcellular organelle, is the site of the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and oxidative phosphorylation (OXPHOS)—the basic processes of ATP production. Mitochondrial function plays a pivotal role in the development and pathology of different cancers. Disruption in its activity, like mutations in its TCA cycle enzymes, leads to physiological imbalances and metabolic shifts of the cell, which contributes to the progression of cancer. In this review, we explored the different significant mutations in the mitochondrial enzymes participating in the TCA cycle and the diseases, especially cancer types, that these malfunctions are closely associated with. In addition, this paper also discussed the different therapeutic approaches which are currently being developed to address these diseases caused by mitochondrial enzyme malfunction.

show abstract

Section: Inhibitors and Drugsmentioning

confidence: 96%

Section: Inhibitors and Drugsmentioning

confidence: 99%

Rescue of TCA Cycle Dysfunction for Cancer Therapy

Marquez

Flores

et al. 2019

JCM

View full text Add to dashboard Cite

show abstract

“…and mIDH1 glioma bearing mice; and mIDH1 glioma bearing mice treated with AGI-5198 was assessed by liquid chromatography-mass spectrometry (UPLC-MS). AGI-5198 (40 mg/kg) was injected intraperitonially (i.p) into mice bearing mIDH1 glioma at 7,9,11,14,16,18,21,23,25 days post tumor cell implantation (dpi). Brains from untreated control mice, wtIDH1 and mIDH1 glioma bearing +/-AGI-5198 treatment were harvested for analysis at 27 dpi.…”

Section: Determination Of 2-hg In Brain Samplesmentioning

confidence: 99%

“…AGI-5198 (40 mg/kg) or saline was injected i.p into mice bearing mIDH1 glioma at 7,9,11,14,16,18,21,23,25 days post tumor cell implantation (dpi). A course of IR (2 Gy) was administered to mice 5 days a week for two weeks starting at 7 dpi (2, 3).…”

Section: In Vivo Cell Cycle Analysismentioning

confidence: 99%

Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity

Kadiyala

Carney

Gauss

et al. 2020

Preprint

View full text Add to dashboard Cite

Brief Summary: Inhibition of 2-Hydroxyglutrate in mutant-IDH1 glioma in the genetic context of ATRX and TP53 inactivation elicits metabolic-reprograming and anti-glioma immunity. Abstract:Mutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas.Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q codeletion/TERT-promoter mutations or (ii) inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work, relates to the gliomas' subtype harboring mIDH1, TP53 and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of 2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma bearing mice. Also, 2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to 2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in wild-type-IDH1 gliomas. Thus, we combined 2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint-blockade and observed complete tumor regression in 60% of mIDH1 glioma bearing mice. This combination strategy reduced T-cell exhaustion and favored the generation of memory CD8 + T-cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data supports the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients. Introduction:Gliomas are highly infiltrative brain tumors accounting for 32% of all primary central nervous system malignancies (1). With advances in molecular biology and sequencing technologies, a distinct profile of genetic alterations for gliomas has emerged (1-3). A gain-offunction mutation in the gene encoding isocitrate dehydrogenase 1 (IDH1) mutation has been reported in ~46% of all adult gliomas (2) and ~80% of low grade gliomas (3, 4). This mutation results in the replacement of arginine (R) for histidine (H) at amino acid residue 132 (R132H) (5, 6). In gliomas, the IDH1-R132H mutation co-occurs with the following genetic alterations: i) oligodendroglioma-1p/19q co-deletion, TERT promoter mutations, or ii) astrocytoma-inactivation of tumor suppressor protein 53 (TP53) gene and loss of function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (ATRX) (2, 4, 7).The IDH1-R132H neomorphic mutation (mIDH1) confers a gain-of-function catalytic activity, prompting the NADPH-dependent reduction of alpha ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (2-HG) (5, 8,9). The accumulation of 2-HG acts antagonistically to α-KG, competitively inhibiting α-KG-dependent dioxygenases, including the ten-eleven translocation (TET) methylcytosine dioxygenases and Jumonji C (JmjC)...

show abstract

“…The physicochemical and pharmacokinetics properties of compounds were measured using the following high-throughput in vitro assays: rat microsomal stability assay, parallel artificial membrane permeability assay (PAMPA) and aqueous kinetic solubility assays. The details of these assays are described in a previous study 14 .…”

Section: In Vitro Adme Studiesmentioning

confidence: 99%

Identification of activators of human fumarate hydratase by quantitative high-throughput screening

Zhu

Lee

Shah

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Fumarate hydratase (FH) is a metabolic enzyme that is part of the Krebs-cycle, and reversibly catalyzes the hydration of fumarate to malate. Mutations of the FH gene have been associated with fumarate hydratase deficiency (FHD), hereditary leiomyomatosis, renal cell cancer (HLRCC), and other diseases. Currently there are no high-quality small molecule probes for studying human fumarate hydratase. To address this, we developed a quantitative high throughput screening (qHTS) FH assay and screened a total of 57,037 compounds from in-house libraries in dose-response. While no inhibitors of FH were confirmed, a series of phenyl-pyrrolopyrimidine-diones were identified as activators of human fumarate hydratase. These compounds were not substrates of fumarate hydratase, were inactive in a malate dehydrogenase counter screen, and showed no detectable reduction-oxidation activity. The binding of two compounds from the series to human fumarate hydratase was confirmed by microscale thermophoresis. The low hit rate in this screening campaign confirmed that FH is a 'tough target' to modulate, and the small molecule activators of human fumarate hydratase reported here may serve as a starting point for further optimization and development into cellular probes of human FH and potential drug candidates. Introduction:Fumarate hydratase (FH) is an important metabolic enzyme in the Krebs-cycle, which reversibly catalyzes the conversion of fumarate to malate (hydration). It is encoded by the FH gene, which produces two isoforms of protein by alternative splicing, a cytosolic form and a mitochondrial form. The mitochondrial form of FH contains a N-terminal mitochondrial targeting sequence, which is removed in the mitochondrion to generate the same protein as that in the cytoplasm.Despite decades of research, a detailed understanding of the mechanism of FH's biochemical activity remains a matter of debate. The active enzyme is a homo-tetramer in which each active site is made up of residues at the interface of three of the four subunits 1 . FH participates in ATP production in mitochondria and the metabolism of amino acids and fumarate in cytoplasm.In humans, mutations of FH gene lead to defects of the enzymatic activity either by indirectly compromising the integrity of the protein's core architecture or directly affecting residues within the active site that regulate catalytic activity of the enzyme 2 . Mutations of FH gene have been mainly associated with two heritable diseases: fumarate hydratase deficiency, and hereditary leiomyomatosis and renal cell cancer (HLRCC). Homozygous germline mutations in FH gene cause autosomal recessive fumarate hydratase deficiency syndrome. It is characterized by early-onset hypotonia, profound psychomotor retardation, seizures, facial dysmorphism and brain abnormalities 3 . Mutations of FH gene severely impair the activity of enzyme which leads to the defect of energy production and the accumulation of fumarate, which is believed to be the cause of clinical symptoms 4 . Heterozygous germline mutati...

show abstract

Assessing inhibitors of mutant isocitrate dehydrogenase using a suite of pre-clinical discovery assays

Cited by 60 publications

References 54 publications

Rescue of TCA Cycle Dysfunction for Cancer Therapy

Rescue of TCA Cycle Dysfunction for Cancer Therapy

Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity

Identification of activators of human fumarate hydratase by quantitative high-throughput screening

Contact Info

Product

Resources

About