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Purity: =99.92%
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.
| Targets |
GLS1 (IC50 = 23 nM); GLS1 (IC50 = 28 nM); GLS2 (IC50 >1 μM)
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|---|---|
| ln Vitro |
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]. |
| ln Vivo |
Telaglenastat (CB-839) (200 mg/kg; p.o.; twice daily for 28 days) exhibits antitumor activity in xenograft models of TNBC[1].
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| Enzyme Assay |
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)).
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| Cell Assay |
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.
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| Animal Protocol |
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 |
| References |
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| Molecular Formula |
C26H24F3N7O3S
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|---|---|
| Molecular Weight |
571.57
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| Exact Mass |
571.16
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| Elemental Analysis |
C, 54.63; H, 4.23; F, 9.97; N, 17.15; O, 8.40; S, 5.61
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| CAS # |
1439399-58-2
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| Related CAS # |
Telaglenastat hydrochloride;1874231-60-3
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| Appearance |
Solid powder
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| SMILES |
C1=CC=NC(=C1)CC(=O)NC2=NN=C(S2)CCCCC3=NN=C(C=C3)NC(=O)CC4=CC(=CC=C4)OC(F)(F)F
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| InChi Key |
PRAAPINBUWJLGA-UHFFFAOYSA-N
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| 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)
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| 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
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| Synonyms |
Telaglenastat; CB839; CB-839; CB 839
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05521997 | Not yet recruiting | Drug: Telaglenastat Drug: Cisplatin |
Cervical Cancer Cervix Cancer |
Washington University School of Medicine |
October 31, 2023 | Phase 2 |
| NCT03798678 | Active Recruiting |
Drug: Carfilzomib Drug: Dexamethasone |
Recurrent Multiple Myeloma Refractory Multiple Myeloma |
National Cancer Institute (NCI) |
July 8, 2019 | Phase 1 |
| NCT03528642 | Active Recruiting |
Drug: Temozolomide Drug: Telaglenastat Hydrochloride |
Astrocytoma, IDH-Mutant, Grade 3 Astrocytoma, IDH-Mutant, Grade 2 |
National Cancer Institute (NCI) |
May 1, 2019 | Phase 1 |
| NCT03872427 | Active Recruiting |
Other: Pharmacodynamic Study Procedure: Biospecimen Collection |
Advanced Malignant Solid Neoplasm Metastatic Malignant Solid Neoplasm |
National Cancer Institute (NCI) |
December 14, 2019 | Phase 2 |
| NCT03831932 | Recruiting | Drug: Telaglenastat Hydrochloride Drug: Osimertinib |
Stage IV Lung Cancer AJCC v8 | National Cancer Institute (NCI) |
March 16, 2020 | Phase 1 Phase 2 |
 FLT3 inhibitor AC220 impairs glutamine flux comparable to the glutaminase inhibitor CB-839 in AML cells.Exp Hematol.2018 Feb;58:52-58. |
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 AC220 and CB-839 have combinatorial effects on cell viability, glutathione, mitochondrial ROS, and apoptosis in AML cells. |
 CB-839 cooperates with AC220 in eliminating FLT3-mutated AML cells in vivo and improves survival.Exp Hematol.2018 Feb;58:52-58. |
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