Design, Synthesis, and Pharmacological Evaluation of Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl Sulfide 3 (BPTES) Analogs as Glutaminase Inhibitors

Shukla, Krupa H.; Ferraris, Dana; Thomas, Ajit G.; Stathis, Marigo; Duvall, Bridget; Delahanty, Greg; Alt, Jesse; Rais, Rana; Rojas, Camilo; Gao, Ping; Xiang, Yan; Dang, Chi V.; Slusher, Barbara S.; Tsukamoto, Takashi

doi:10.1021/jm301191p

Cited by 165 publications

(183 citation statements)

References 28 publications

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“…Combination of CB-839 with paclitaxel largely suppressed the regrowth of the tumors resulting in a TGI relative to vehicle control of 100% at the end of study (P < 0.0001 vs. vehicle and P ¼ 0.0025 vs. paclitaxel alone). These in vivo efficacy results build upon those previously published using other glutaminase inhibitors in lymphoma and renal cancer models (6,9,13,19).…”

Section: Tnbc Cell Lines Are Sensitive To Glutaminase Inhibition Withsupporting

confidence: 79%

“…The small-molecule BPTES was previously described as an allosteric glutaminase inhibitor active against both splice variants of the GLS gene, GAC and KGA (reported Ki between 0.2 and 3 mmol/L), but not the liver form of glutaminase, encoded by the GLS2 gene (18,19,21,22). CB-839 (Fig.…”

Section: Cb-839 Is a Potent And Selective Glutaminase Inhibitormentioning

confidence: 99%

“…Several small-molecule inhibitors of glutaminase have been reported (6,(17)(18)(19). Glutamine analogs, 6-diazo-5-oxo-L-norleucine, azaserine and acivicin, bind irreversibly to the active site of a number of glutamine-utilizing enzymes, including glutaminase (20).…”

Section: Introductionmentioning

confidence: 99%

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Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer

Gross

Demo

Dennison

et al. 2014

Molecular Cancer Therapeutics

801

896

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Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activity was observed in an estrogen receptor-positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GAC protein expression and glutaminase activity were elevated in the majority of TNBC cell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii) GAC (but not KGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2 þ cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors. Mol Cancer Ther; 13(4); 890-901. Ó2014 AACR.

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Section: Tnbc Cell Lines Are Sensitive To Glutaminase Inhibition Withsupporting

confidence: 79%

Section: Cb-839 Is a Potent And Selective Glutaminase Inhibitormentioning

confidence: 99%

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Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer

Gross

Demo

Dennison

et al. 2014

Molecular Cancer Therapeutics

801

896

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“…The first major structure-activity relationship (SAR) study around BPTES was reported in 2012 by Shukla et al, and focused on alteration of the flexible chain in the center of the molecule and desymmetrization via replacement of one or both phenyl groups at the ends of the molecule [125]. The key findings were that the central linker could be replaced by a four carbon chain, and that one, but not both, phenyl groups could be removed to enhance solubility without significantly reducing potency ( Figure 7, Shukla_11b, Shukla_5).…”

Section: Kidney-type Glutaminase: Drug Discoverymentioning

confidence: 99%

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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“…BPTES is a selective inhibitor of glutaminase 1 (27,61,62). Our results suggest that inhibition of glutaminase 1 can have an antitumorigenic effect on RCC and that MYCassociated RCC is glutamine addicted.…”

Section: Discussionmentioning

confidence: 61%

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

Shroff¹,

Eberlin

Dang

et al. 2015

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

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The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.MYC oncogene | renal cell carcinoma | desorption electrospray ionization mass spectrometry imaging | glutamine metabolism R enal cell adenocarcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport waste molecules from the blood to the urine. Most patients who present with advanced RCC have a dismal prognosis because RCC easily metastasizes and advances in therapy have been limited (1-3). A lack of transgenic models of RCC has made it difficult to identify and test new therapeutic modalities.The MYC pathway is activated in most cases of human RCC (4), genomically amplified in 5-10% of patients, overexpressed in 20% (5), and associated with a hereditary RCC syndrome (6) suggesting a causal role in the pathogenesis, but this has never been examined. Here, we report the development of a conditional transgenic mouse model for MYC-deregulated human RCC. The MYC oncogene contributes to tumorigenesis of many types of cancer through various mechanisms (7-10), including the regulation of proliferation and growth, protein and ribosomal biogenesis, changes in metabolism, lipid synthesis, and induction of angiogenesis (11)(12)(13)(14). MYC reprogramming can result in tumors that are addicted to glucose and/or glutamine for their energy metabolism (15-19). MYC directly regulates specific genes of the glycolytic and glutaminolytic pathways (15,17,20,21), including lactate dehydrogenase A (LDHA), glucose transporter 1 (Glut1), hexokinase 2 (HK2), phosphofructokinase-M 1 (PFKM1), and enolase 1 (Eno1) (21-23). Also, MYC coordinates genes involved in glutamine catabolism (SI MYC and Glutamine Catabolism). However, there has been no evidence to show that MYC overexpression directly drives and maintains RCC or how this occurs.Through our new transgenic mouse model, we showed that transgenic MYC, but not mutant RAS, overexpression in vivo rapidly initiates a highly aggressive RCC that histologi...

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Design, Synthesis, and Pharmacological Evaluation of Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl Sulfide 3 (BPTES) Analogs as Glutaminase Inhibitors

Cited by 165 publications

References 28 publications

Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer

Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer

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

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

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