Allosteric Glutaminase Inhibitors Based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane Scaffold

Zimmermann, Sarah C.; Wolf, Emily F.; Luu, Andrew; Thomas, Ajit G.; Stathis, Marigo; Poore, Brad; Nguyen, Christopher; Le, Anne; Rojas, Camilo; Slusher, Barbara S.; Tsukamoto, Takashi

doi:10.1021/acsmedchemlett.6b00060

Cited by 49 publications

(51 citation statements)

References 15 publications

(28 reference statements)

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“…Further, the drug exhibits an as-yet-unexplained requirement to be incubated for up to 4 h with GLS before it exhibits maximum potency. Very similar series of compounds were described in a report from Zimmermann and coworkers, and in patents from Agios (MA, USA) and the University of Texas, with representative examples shown in Figure 7 [127][128][129][130][131][132].…”

Section: Kidney-type Glutaminase: Drug Discoverymentioning

confidence: 85%

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

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Many cancer cells exhibit an altered metabolic phenotype, in which glutamine consumption is upregulated relative to healthy cells. This metabolic reprogramming often depends upon mitochondrial glutaminase activity, which converts glutamine to glutamate, a key precursor for biosynthetic and bioenergetic processes. Two isozymes of glutaminase exist, a kidney-type (GLS) and a liver-type enzyme (GLS2 or LGA). While a majority of studies have focused on GLS, here we summarize key findings on both glutaminases, describing their structure and function, their roles in cancer and pharmacological approaches to inhibiting their activities.

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Section: Kidney-type Glutaminase: Drug Discoverymentioning

confidence: 85%

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

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“…GLS inhibitors used to target GLS directly are 6-diazo-5-oxy-L-norleucine (DON), 968, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulphide (BPTES), and 2-(pyridin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy) phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide (CB-839). 1,58,71 Glutaminase Isoforms…”

Section: Glutamine Metabolism and Addiction In Cancermentioning

confidence: 99%

“…53,56 In terms of inhibition of GLS, CB-839 is a more potent compound than BPTES. 28,55,58 In addition, CB-839 has inhibitory concentrations 30fold and 50-fold lower than those of BPTES. 62 Preclinical models have demonstrated that CB-839 causes significant growth inhibition in certain subtypes of BC.…”

Section: Glutaminase Inhibitorsmentioning

confidence: 99%

The role of glutaminase in cancer

et al. 2020

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Increased glutamine metabolism (glutaminolysis) is a hallmark of cancer and is recognised as a key metabolic change in cancer cells. Breast cancer is a heterogeneous disease with different morphological and molecular subtypes and responses to therapy, and breast cancer cells are known to rewire glutamine metabolism to support survival and proliferation. Glutaminase isoenzymes (GLS and GLS2) are key enzymes for glutamine metabolism. Interestingly, GLS and GLS2 have contrasting functions in tumorigenesis. In this review, we explore the role of glutaminase in cancer, primarily focusing on breast cancer, address the role played by oncogenes and tumour suppressor genes in regulating glutaminase, and discuss current therapeutic approaches to targeting glutaminase.

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“…PLGA and PEG are each widely used in pharmaceutical products and have a long history of safe human use (34,35). Thus, nanoparticle encapsulation may be useful as a means to improve the pharmacokinetics and efficacy of other GLS inhibitors, including CB-839 (18), as well as newer and more potent inhibitors (36). This therapeutic strategy may be applicable to other glutamine-dependent tumors, including those with fumarate hydratase deficiency, succinate dehydrogenase deficiency, or mutant isocitrate dehydrogenase 1 or 2.…”

Section: Combined Bptes-np and Metformin Treatment Provides Enhancedmentioning

confidence: 99%

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

Elgogary

Poore

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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188

159

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Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.pancreatic ductal adenocarcinoma | glutaminolysis | glucose metabolism | KRAS mutation | intratumoral hypoxia P atients with pancreatic ductal adenocarcinoma (PDAC) have among the highest fatality rates of all cancers (1). Pancreatic cancer is predicted to become the second-leading cause of cancer death in the United States by the year 2030 (2). Over 90% of PDACs display mutations in oncogenic KRAS (Kirsten rat sarcoma viral oncogene homolog) (3, 4), a known regulator of glutamine metabolism that can render cancer cells dependent on glutamine for survival and proliferation (5, 6)-a state known as "glutamine addiction" (7, 8)-suggesting that dependency on glutamine could be exploited to develop new therapies for KRAS-mutated PDAC. The first step of glutamine metabolism is the conversion of glutamine to glutamate and ammonia, which is catalyzed by glutaminase (GLS). Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), which is an allosteric, time-dependent (9), and specific inhibitor of GLS1, exhibits unique binding at the oligomerization interface of the glutaminase tetramer (10, 11). Although BPTES is more selective than other prototype glutaminase inhibitors, such as 6-diazo-5-oxo-L-norleucine (12) or ebselen (9), and can effectively inhibit GLS1 (13) and tumor growth (13-15), poor solubility (0.144 μg/mL) (16) has limited its clinical development. Recently, CB-839 (17) was tested in a phase I clinical trial. Abnormal liver and kidney function tests, lymphop...

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Allosteric Glutaminase Inhibitors Based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane Scaffold

Cited by 49 publications

References 15 publications

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

The role of glutaminase in cancer

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

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