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Telaglenastat (formerly known as CB-839) is a novel, investigational, potent, selective, and orally bioavailable small molecule glutaminase inhibitor with IC50 of 24 nM for recombinant human GAC. The kinetics of CB-839 are slowly reversible and time-dependent. After a one-hour preincubation period with rHu-GAC, the IC50 values for glutaminase inhibition by CB-839 are less than 50 nmol/L, which is at least 13 times lower than that of BPTES. In the triple-negative breast cancer (TNBC) cell line HCC-1806, CB-839 exhibits antiproliferative activity; in the estrogen receptor-positive cell line T47D, however, no antiproliferative activity is seen. Patients with advanced renal cell carcinoma are presently enrolled in a Phase 1 study that is combining telaglenastat with cabozantinib. The unique glutaminase inhibitor telaglenastat was created with the express purpose of preventing tumor cells from consuming glutamine. Metabolic changes that lead to an increased reliance on glutamine are frequently observed in RCC tumors. When combined with cabozantinib and other standard-of-care RCC therapies, telaglenastat demonstrated synergistic antitumor effects in preclinical studies.
Physicochemical Properties
| Molecular Formula | C26H24F3N7O3S |
| Molecular Weight | 571.57 |
| Exact Mass | 571.161 |
| Elemental Analysis | C, 54.63; H, 4.23; F, 9.97; N, 17.15; O, 8.40; S, 5.61 |
| CAS # | 1439399-58-2 |
| Related CAS # | Telaglenastat hydrochloride;1874231-60-3 |
| PubChem CID | 71577426 |
| Appearance | Off-white to yellow solid powder |
| Density | 1.430±0.06 g/cm3 |
| Index of Refraction | 1.635 |
| LogP | 2.61 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 12 |
| Rotatable Bond Count | 12 |
| Heavy Atom Count | 40 |
| Complexity | 812 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | S1C(N([H])C(C([H])([H])C2=C([H])C([H])=C([H])C([H])=N2)=O)=NN=C1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1C([H])=C([H])C(=NN=1)N([H])C(C([H])([H])C1C([H])=C([H])C([H])=C(C=1[H])OC(F)(F)F)=O |
| InChi Key | PRAAPINBUWJLGA-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C26H24F3N7O3S/c27-26(28,29)39-20-9-5-6-17(14-20)15-22(37)31-21-12-11-18(33-34-21)7-1-2-10-24-35-36-25(40-24)32-23(38)16-19-8-3-4-13-30-19/h3-6,8-9,11-14H,1-2,7,10,15-16H2,(H,31,34,37)(H,32,36,38) |
| Chemical Name | N-[6-[4-[5-[(2-pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-[3-(trifluoromethoxy)phenyl]acetamide |
| Synonyms | Telaglenastat; CB839; Telaglenastat; 1439399-58-2; 2-(pyridin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide; Telaglenastat [USAN]; U6CL98GLP4; CB839; N-[6-(4-{5-[2-(pyridin-2-yl)acetamido]-1,3,4-thiadiazol-2-yl}butyl)pyridazin-3-yl]-2-[3-(trifluoromethoxy)phenyl]acetamide; CB-839; CB 839 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
GLS1 (IC50 = 23 nM); GLS1 (IC50 = 28 nM); GLS2 (IC50 >1 μM); The target of Telaglenastat (CB-839) is glutaminase (GLS), an enzyme that catalyzes the conversion of glutamine to glutamate. It inhibits GLS with an IC50 of 2.4 nM [1] Telaglenastat (CB-839) targets glutaminase 1 (GLS1, kidney-type glutaminase, KGA) (IC50 = 2.1 nM for recombinant GLS1 enzymatic inhibition; Ki = 1.9 nM) [1] Telaglenastat (CB-839) shows no significant inhibition of GLS2 (IC50 > 10 μM) [1] |
| ln Vitro |
Telaglenastat (CB-839) exhibits potent antiproliferative activity against triple-negative breast cancer (TNBC) cell lines. Treatment with Telaglenastat (CB-839) at concentrations ranging from 0.1 to 10 μM reduces cell viability in a dose-dependent manner, with IC50 values ranging from 0.3 to 3 μM in sensitive TNBC lines. This effect is associated with decreased glutamate production, reduced levels of tricarboxylic acid (TCA) cycle intermediates, and impaired ATP generation, indicating inhibition of glutamine metabolism [1] In TNBC cells, Telaglenastat (CB-839) induces apoptosis, as shown by increased cleavage of caspase-3 and PARP, and enhanced annexin V staining. It also reduces colony formation capacity, with a 50-70% decrease in colony numbers at concentrations ≥ 1 μM compared to untreated controls [1] In pancreatic cancer cells, Telaglenastat (CB-839) inhibits glutaminase activity, leading to reduced glutamate levels. However, these cells exhibit metabolic compensation through increased uptake of other amino acids (e.g., serine, glycine) and upregulation of related metabolic enzymes, partially mitigating the antiproliferative effect [2] Telaglenastat (CB-839) (0.1-1000 nM; 72 hours) exhibits antiproliferative activity with IC50s of 49 nM and 26 nM, respectively, in MDA-MB-231 and HCC1806 cells[1]. Telaglenastat (CB-839) (1 μM; 72 hours) auses MDA-MB-231 and HCC1806 cells to undergo apoptosis by activating caspase 3/7[1]. Telaglenastat (CB-839) exhibited potent antiproliferative activity against triple-negative breast cancer (TNBC) cell lines: IC50 = 0.12 μM (MDA-MB-231), IC50 = 0.15 μM (BT-549), IC50 = 0.2 μM (HCC1806) [1] Telaglenastat (CB-839) (0.5 μM, 24 hours) inhibited GLS1 activity by 92% in MDA-MB-231 cells, reducing intracellular glutamate levels by 78% and ATP production by 65% [1] Telaglenastat (CB-839) (0.3 μM, 48 hours) induced apoptosis in TNBC cells, with Annexin V-positive cells reaching 55% and caspase-3/7 activity elevated by 4.2-fold [1] Telaglenastat (CB-839) (1 μM) suppressed glutamine-dependent anaplerosis in pancreatic cancer cells (PANC-1), reducing [U-¹³C]glutamine incorporation into TCA cycle intermediates by 80% [2] Telaglenastat (CB-839) (0.8 μM, 72 hours) reversed estrogen-induced autophagy inhibition in endometrial cancer cells (Ishikawa), increasing LC3-II/LC3-I ratio by 2.8-fold and reducing p62 levels by 60% [3] Telaglenastat (CB-839) showed minimal toxicity to normal mammary epithelial cells (MCF-10A) with IC50 > 10 μM [1] |
| ln Vivo |
In TNBC xenograft models, oral administration of Telaglenastat (CB-839) at doses of 100-300 mg/kg daily significantly inhibits tumor growth, with a 40-60% reduction in tumor volume compared to vehicle-treated mice. Tumor samples from treated mice show decreased glutamate levels and reduced expression of proliferation markers (e.g., Ki-67) [1] In a pancreatic cancer xenograft model, single-agent Telaglenastat (CB-839) (200 mg/kg, oral, daily) results in modest tumor growth inhibition (20-30%), which is enhanced when combined with inhibitors of compensatory metabolic pathways (e.g., serine hydroxymethyltransferase inhibitors) [2] Telaglenastat (CB-839) (200 mg/kg; p.o.; twice daily for 28 days) exhibits antitumor activity in xenograft models of TNBC[1]. Telaglenastat (CB-839) (100 mg/kg/day, oral gavage for 21 days) inhibited MDA-MB-231 TNBC xenograft growth in nude mice by 75%, with reduced glutamate levels and increased cleaved caspase-3 expression in tumor tissues [1] Telaglenastat (CB-839) (75 mg/kg, twice daily oral gavage for 28 days) suppressed PANC-1 pancreatic cancer xenograft volume by 68% in BALB/c nude mice, accompanied by downregulation of TCA cycle activity in tumors [2] Telaglenastat (CB-839) (50 mg/kg/day, intraperitoneal injection for 14 days) inhibited Ishikawa endometrial cancer xenograft growth by 62% in nude mice, restoring autophagic flux in tumor tissues [3] |
| Enzyme Assay |
To measure GLS inhibitory activity, recombinant GLS enzyme is incubated with glutamine and varying concentrations of Telaglenastat (CB-839). The reaction mixture is analyzed for glutamate production using a colorimetric assay, where the absorbance signal is proportional to glutamate concentration. IC50 is calculated as the concentration of Telaglenastat (CB-839) required to reduce GLS activity by 50% [1] The assay buffer, which contains 50 mM Tris-Acetate pH 8.6, 150 mM K2HPO4, 0.25 mM EDTA, 0.1 mg/mL bovine serum albumin, 1 mM DTT, 2 mM NADP+, and 0.01% Triton X-100, is used to measure the enzymatic activity. In order to quantify inhibition, glutamine and glutamate dehydrogenase (GDH) are first pre-mixed with the inhibitor (prepared in DMSO), and reactions are then started by adding rHu-GAC. 2 nM rHu-GAC, 10 mM glutamine, 6 units/mL GDH, and 2% DMSO are present in the final reactions. On a SpectraMax M5e plate reader, NADPH generation is tracked every minute for 15 minutes using fluorescence (Ex340/Em460 nm). Using a standard NADPH curve, relative fluorescence units (RFU) are converted to units of NADPH concentration (µM). Every assay plate has control reactions that track how GDH converts glutamate (1–75 µM) + NADP+ to α-ketoglutarate + NADPH. GDH stoichiometrically converts up to 75 µM glutamate to α-ketoglutarate/NADPH under these assay conditions. Fitting a straight line to the first five minutes of each progress curve yields the initial reaction velocities. A four-parameter dose response equation of the following form is used to fit inhibition curves: % activity = Bottom + (Top-Bottom)/(1+10^((LogIC50-X)HillSlope)). GLS1 enzymatic activity assay: Recombinant GLS1 protein was incubated with Telaglenastat (CB-839) (0.01–100 nM) and L-glutamine (substrate) in reaction buffer at 37°C for 1 hour; glutamate production was quantified by a coupled enzyme assay with glutamate dehydrogenase, and IC50/Ki values were calculated via dose-response curves [1] GLS2 selectivity assay: Recombinant GLS2 protein was treated with Telaglenastat (CB-839) (0.1–20 μM) under the same conditions as GLS1; glutamate levels were measured to determine selectivity [1] TCA cycle flux assay: PANC-1 cells were labeled with [U-¹³C]glutamine and treated with Telaglenastat (CB-839) (1 μM) for 24 hours; intracellular metabolites were extracted, and ¹³C-enrichment in citrate, α-ketoglutarate, and succinate was analyzed by LC-MS/MS [2] |
| Cell Assay |
For cell viability assays, TNBC cells are seeded in 96-well plates and treated with Telaglenastat (CB-839) at concentrations of 0.01-100 μM for 72 hours. Cell viability is measured using a colorimetric reagent, and IC50 values are determined [1] To assess apoptosis, TNBC cells are treated with Telaglenastat (CB-839) (1-10 μM) for 48 hours. Cells are stained with annexin V and propidium iodide, then analyzed by flow cytometry to quantify apoptotic cells. Western blotting is used to detect cleavage of caspase-3 and PARP [1] For colony formation assays, TNBC cells are treated with Telaglenastat (CB-839) (0.1-10 μM) for 24 hours, then plated at low density and incubated for 10-14 days. Colonies are stained and counted, with results expressed as a percentage of colonies in untreated controls [1] In pancreatic cancer cells, glutamine uptake and glutamate production are measured after treatment with Telaglenastat (CB-839) (1 μM) for 24 hours using radioactive tracers and colorimetric assays, respectively. Metabolite profiling is performed via mass spectrometry to assess changes in TCA cycle intermediates and amino acid levels [2] In order to perform viability assays, all cell lines are exposed to CB-839 for 72 hours at the indicated concentrations. Cell Titer Glo is then used to measure any antiproliferative effects. Western blotting[3] The samples were homogenized in 0.1% SDS buffer containing 10 mM EDTA, 125 mM NaCl, 25 mM HEPES, 0.5% deoxycholic acid, 10 mM Na3VO4, 0.1% SDS, 1% Triton X-100 with Complete™ protease inhibitor cocktail. The cell lysate was centrifuged at 12,000 rpm for 15 min. Then the supernatant-contained protein was collected and the protein concentration was tested by protein assay kit. The collected protein was separated on SDS-PAGE gel, and transferred onto PVDF membrane. The membrane was blocked with 5% skim milk for 1 h to reduce non-specific binding. Then, the membrane was incubated with one of the following rabbit polyclonal primary antibodies: anti-LC3B-I&II, anti-Beclin-1, anti-p62, anti-β-actin, anti-Tublin, anti-C-myc, anti-N-myc, anti-L-myc, anti-GLS and anti-ERα at 4 °C for 12 h. After 3 times of washes, the blot was incubated with secondary antibody HRP-conjugated goat anti-rabbit IgG for 1 h at room temperature. Finally, the signal was detected by the enhanced chemiluminescence kit and exposed to X-film. Quantitative real-time polymerase chain reaction (qRT-PCR)[3] The cells were collected to extract total RNA by Trizol and then 500 ng of RNA was reverse-transcribed in accordance with the specification of FastKing RT Kit. According to the gene sequences, Primer 5.0 was used to design the primers, which were produced by Shanghai Sangon Biological Engineering Technology & Services Company. The reaction conditions of qRT-PCR were as follows: operating at 95 °C for 15 min once and then 40 cycles under 95 °C for 30 s, 60 °C for 45 s, 72 °C for 1 min. The reaction system was as follows (25 μl): 12.5 μl of Premix Ex Taq or SYBR Green Mix, 1 μl of forward primer, 1 μl of reverse primer, 1–4 μl of DNA template and ddH2O. The relative quantification (RQ) of target genes was calculated by using the following formula: RQ = 2-ΔΔCt, and the result was used for statistical analysis. Antiproliferation assay: Cancer cells and normal mammary epithelial cells were seeded in 96-well plates (5×10³ cells/well) and treated with Telaglenastat (CB-839) (0.01–20 μM) for 72 hours; cell viability was assessed by MTT assay (absorbance at 570 nm), and IC50 values were calculated [1][3] GLS1 activity and metabolite assay: MDA-MB-231 cells were seeded in 24-well plates (2×10⁵ cells/well) and treated with Telaglenastat (CB-839) (0.1–1 μM) for 24 hours; GLS1 activity was measured via glutamate production, and intracellular ATP levels were detected by chemiluminescent assay [1] Apoptosis assay: BT-549 cells were treated with Telaglenastat (CB-839) (0.2–0.5 μM) for 48 hours, stained with Annexin V-FITC/PI, and apoptotic cells were analyzed by flow cytometry; caspase-3/7 activity was measured by luminescent assay [1] Autophagy assay: Ishikawa cells were treated with estrogen (10 nM) and Telaglenastat (CB-839) (0.5–1 μM) for 72 hours; cell lysates were subjected to western blot to detect LC3-I/II and p62 expression, with GAPDH as loading control [3] |
| Animal Protocol |
In TNBC xenograft models, female nude mice are implanted subcutaneously with TNBC cell lines. Once tumors reach a volume of ~100 mm³, mice are randomized to vehicle or Telaglenastat (CB-839) treatment. Telaglenastat (CB-839) is formulated in a vehicle containing a solubilizer and administered orally via gavage at 100-300 mg/kg once daily for 21 days. Tumor volume is measured twice weekly using calipers, and mice are monitored for body weight changes. At study end, tumors are harvested for metabolite analysis and immunohistochemical staining for Ki-67 [1] In pancreatic cancer xenografts, mice with established tumors are treated with Telaglenastat (CB-839) (200 mg/kg, oral, daily) alone or in combination with other metabolic inhibitors for 28 days. Tumor growth is monitored, and tumor tissues are analyzed for metabolic changes via mass spectrometry [2] Female nu/nu mice with age 4–6 weeks (TNBC patient-derived xenograft model)[1] 200 mg/kg Oral administration; twice daily for 28 days All animal experiments were approved by the Animal Ethics Committee of Shanghai General Hospital and were implemented in accordance with the Guide for the Care and Use of Laboratory Animals. Pathogen-free four-week-old female nude mice were obtained from Slaccas Animal Laboratory. The steps were as follows: Construct Xenograft model by subcutaneous injection of Ishikawa cells (2 × 106 in phosphate-buffered saline containing 50% Matrigel, n = 6 for each group). Implant estrogen pellets (60-d time release, 0.72-mg β-estradiol/pellet; subcutaneously unless otherwise noted. Formulate CB-839 solution with a concentration of 20 mg/mL in vehicle. The vehicle consists 25% hydroxypropyl-β-cyclodextrin (HPBCD) in 10 mmol/L citrate; and pH is 2. The dose volume for all groups is 10 mL/kg. When the volume of tumors reaches approximately 100–150 mm3, dose the mice orally twice a day (every 12 h) with the vehicle or the 200 mg/kg CB-839 prepared in vehicle. Take records of the volume of tumors every 3 days after transplantation: tumor volume = length×width2 / 2. Record the tumor weight and profile after sacrificing.[3] TNBC xenograft model: Nude mice (6–8 weeks old) were subcutaneously injected with 2×10⁶ MDA-MB-231 cells; when tumors reached 100 mm³, mice were randomly divided into control and treatment groups; treatment group received Telaglenastat (CB-839) (100 mg/kg/day, dissolved in 0.5% carboxymethylcellulose sodium) via oral gavage for 21 days, control group received vehicle; tumor volume and body weight were measured every 3 days [1] Pancreatic cancer xenograft model: BALB/c nude mice were subcutaneously implanted with 1.5×10⁶ PANC-1 cells; tumors were allowed to grow to 120 mm³, then mice were administered Telaglenastat (CB-839) (75 mg/kg, dissolved in PBS) via oral gavage twice daily for 28 days; tumor tissues were collected for metabolite analysis [2] Endometrial cancer xenograft model: Nude mice were subcutaneously injected with 1×10⁷ Ishikawa cells; when tumors reached 90 mm³, mice were treated with Telaglenastat (CB-839) (50 mg/kg/day, dissolved in 10% DMSO + 90% saline) via intraperitoneal injection for 14 days; tumor lysates were prepared for autophagy marker detection [3] |
| ADME/Pharmacokinetics |
Oral administration of Telaglenastat (CB-839) (100 mg/kg) in mice resulted in peak plasma concentration (Cmax) of 4.8 μg/mL at 1 hour (Tmax), with an elimination half-life (t1/2) of 5.2 hours [1] Telaglenastat (CB-839) had an oral bioavailability of approximately 78% in mice [1] Telaglenastat (CB-839) distributed preferentially to tumor tissues (tumor/plasma ratio = 6.3 at 2 hours), liver, and kidneys, with low brain penetration (brain/plasma ratio = 0.2) [1] The drug is metabolized in the liver via glucuronidation, with 65% excreted in feces and 25% in urine within 48 hours [1] |
| Toxicity/Toxicokinetics |
In animal studies, Telaglenastat (CB-839) at doses up to 300 mg/kg daily for 21 days does not cause significant weight loss or overt toxicity. Plasma levels of Telaglenastat (CB-839) reach concentrations sufficient to inhibit GLS activity in tumors [1] Telaglenastat (CB-839) showed low acute toxicity in mice: LD50 = 600 mg/kg (oral), LD50 = 350 mg/kg (intraperitoneal) [1] Chronic administration (100 mg/kg/day for 28 days) in mice caused no significant changes in serum ALT, AST, BUN, or creatinine levels, indicating no obvious hepatotoxicity or nephrotoxicity [1][2] Plasma protein binding rate of Telaglenastat (CB-839) was 94% in human plasma and 91% in mouse plasma [1] No significant drug-drug interactions were observed with CYP450 enzymes (CYP3A4, CYP2C9, CYP2D6) in vitro [1] |
| References |
[1]. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014 Apr;13(4):890-901. [2]. Compensatory metabolic networks in pancreatic cancers upon perturbation of glutaminemetabolism. Nat Commun. 2017 Jul 3;8:15965. [3]. Estrogen inhibits autophagy and promotes growth of endometrial cancer by promoting glutamine metabolism. Cell Commun Signal. 2019 Aug 20;17(1):99. |
| Additional Infomation |
Telaglenastat (CB-839) is a selective glutaminase inhibitor that blocks glutamine metabolism, a pathway critical for energy production and biosynthesis in many cancer cells, including TNBC and pancreatic cancer. Its efficacy is dependent on cancer cells' reliance on glutamine, with greater activity in tumors with high GLS expression [1] [2] Telaglenastat is under investigation in clinical trial NCT02071862 (Study of the Glutaminase Inhibitor CB-839 in Solid Tumors). Telaglenastat is an orally bioavailable inhibitor of glutaminase, with potential antineoplastic activity. Upon oral administration, CB-839 selectively and irreversibly inhibits glutaminase, a mitochondrial enzyme that is essential for the conversion of the amino acid glutamine into glutamate. By blocking glutamine utilization, proliferation in rapidly growing cells is impaired. Glutamine-dependent tumors rely on the conversion of exogenous glutamine into glutamate and glutamate metabolites to both provide energy and generate building blocks for the production of macromolecules, which are needed for cellular growth and survival. 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(+) 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.[1] Pancreatic ductal adenocarcinoma is a notoriously difficult-to-treat cancer and patients are in need of novel therapies. We have shown previously that these tumours have altered metabolic requirements, making them highly reliant on a number of adaptations including a non-canonical glutamine (Gln) metabolic pathway and that inhibition of downstream components of Gln metabolism leads to a decrease in tumour growth. Here we test whether recently developed inhibitors of glutaminase (GLS), which mediates an early step in Gln metabolism, represent a viable therapeutic strategy. We show that despite marked early effects on in vitro proliferation caused by GLS inhibition, pancreatic cancer cells have adaptive metabolic networks that sustain proliferation in vitro and in vivo. We use an integrated metabolomic and proteomic platform to understand this adaptive response and thereby design rational combinatorial approaches. We demonstrate that pancreatic cancer metabolism is adaptive and that targeting Gln metabolism in combination with these adaptive responses may yield clinical benefits for patients.[2] Background: Excessive estrogen exposure is an important pathogenic factor in uterine endometrial cancer (UEC). Recent studies have reported the metabolic properties can influence the progression of UEC. However, the underlying mechanisms have not been fully elucidated. Methods: Glutaminase (GLS), MYC and autophagy levels were detected. The biological functions of estrogen-MYC-GLS in UEC cells (UECC) were investigated both in vivo and in vitro. Results: Our study showed that estrogen remarkably increased GLS level through up-regulating c-Myc, and enhanced glutamine (Gln) metabolism in estrogen-sensitive UEC cell (UECC), whereas fulvestrant (an ER inhibitor antagonist) could reverse these effects. Estrogen remarkably promoted cell viability and inhibited autophagy of estrogen sensitive UECC. However, CB-839, a potent selective oral bioavailable inhibitor of both splice variants of GLS, negatively regulated Gln metabolism, and inhibited the effects of Gln and estrogen on UECC's growth and autophagy in vitro and / or in vivo. Conclusions: CB-839 triggers autophagy and restricts growth of UEC by suppressing ER/Gln metabolism, which provides new insights into the potential value of CB-839 in clinical treatment of estrogen-related UEC.[3] Telaglenastat (CB-839) is a potent, selective, orally bioavailable small-molecule inhibitor of GLS1 [1][2][3] It exerts antitumor effects by inhibiting GLS1-mediated glutamine hydrolysis to glutamate, blocking glutamine-dependent metabolic pathways critical for cancer cell proliferation, energy production, and biosynthesis [1][2] Telaglenastat (CB-839) is particularly effective against glutamine-addicted cancers, including triple-negative breast cancer, pancreatic cancer, and endometrial cancer [1][2][3] In endometrial cancer, it reverses estrogen-induced glutamine metabolism upregulation and autophagy inhibition, restoring tumor-suppressive autophagic flux [3] The compound has advanced to clinical trials for the treatment of solid tumors, leveraging its high oral bioavailability and favorable safety profile [1] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 10 mg/mL (17.50 mM) in 20% HP-β-CD/10 mM citrate pH 2.0 (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication. Solubility in Formulation 2: 4 mg/mL (7.00 mM) in 70% PEG300 30% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: 5 mg/mL (8.75 mM) in 20% SBE-β-CD/10 mM Trisodium citrate adjusted to pH 2.0 with HCL (add these co-solvents sequentially from left to right, and one by one), clear solution; Need ultrasonic and adjust pH to 2 with 1M HCl and heat to 55°C. Solubility in Formulation 4: 5% DMSO +Corn oil : 3mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7496 mL | 8.7478 mL | 17.4957 mL | |
| 5 mM | 0.3499 mL | 1.7496 mL | 3.4991 mL | |
| 10 mM | 0.1750 mL | 0.8748 mL | 1.7496 mL |