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Telaglenastat HCl (formerly CB839; CB-839) is an orally bioavailable small molecule glutaminase inhibitor with anticancer activity. It inhibits glutaminase with IC50 of 24 nM for recombinant human GAC. CB-839 exhibits time-dependent and slowly reversible kinetics. IC50 values for glutaminase inhibition by CB-839 following preincubation with rHu-GAC for-1 hour are < 50 nmol/L, at least 13-fold lower than with BPTES. CB-839 has antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, while no antiproliferative activity is observed in an estrogen receptor–positive cell line, T47D. Telaglenastat is currently in Phase 1 study in combination with cabozantinib in patients with advanced renal cell carcinoma. Telaglenastat is novel glutaminase inhibitor specifically designed to block glutamine consumption in tumor cells. RCC tumors commonly exhibit metabolic alterations that increase their dependence on glutamine. In preclinical studies, telaglenastat produced synergistic antitumor effects when used in combination with standard-of-care RCC therapies including cabozantinib.
| Targets |
GLS1 (IC50 = 23 nM); GLS1 (IC50 = 28 nM); GLS2 (IC50 >1 μM)
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| ln Vitro |
In HCC1806 and MDA-MB-231 cells, telaglenastat (CB-839) (0.1-1000 nM; 72 hours) exhibits antiproliferative activity with IC50s of 49 nM and 26 nM, respectively[1]. MDA-MB-231 and HCC1806 cells undergo apoptosis when exposed to telaglenastat (CB-839) (1 μM; 72 hours) because it activates caspase 3/7[1].
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| ln Vivo |
In TNBC xenograft models, telaglenastat (CB-839) (200 mg/kg; po; twice daily for 28 days) exhibits anticancer activity[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 |
Cell Proliferation Assay[1]
Cell Types: HCC1806, MDA-MB-231 cells Tested Concentrations: 0.1, 1, 10, 100, 1000 nM Incubation Duration: 72 hrs (hours) Experimental Results: Has a potent effect on the proliferation of the two TNBC cell lines (IC50 of 49 nM and 26 nM for HCC1806 and MDA-MB-231 cells). Apoptosis Analysis[1] Cell Types: MDA-MB-231, HCC1806 cells Tested Concentrations: 1 μM Incubation Duration: 72 hrs (hours) Experimental Results: Caspase 3/7 activation. |
| Animal Protocol |
Animal/Disease Models: Female nu/nu (nude) mice with age 4–6 weeks (TNBC patient- derived xenograft model)[1]
Doses: 200 mg/kg Route of Administration: Oral administration; twice (two times) daily for 28 days Experimental Results: Suppressed tumor growth by 61% relative to vehicle control at the end of study. |
| References |
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| Additional Infomation |
Telaglenastat Hydrochloride is the hydrochloride salt form of CB-839, an orally bioavailable inhibitor of glutaminase, with potential antineoplastic and immunostimulating activities. Upon oral administration, CB-839 selectively and reversibly binds to and inhibits human glutaminase, an enzyme that is essential for the conversion of the amino acid glutamine into glutamate. Blocking glutamine metabolism inhibits proliferation in rapidly growing tumor cells and leads to an induction of cell death. Unlike normal healthy cells, glutamine-dependent tumors heavily rely on the intracellular 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. In addition, CB-839 causes accumulation of glutamine in tumor cells and increases glutamine concentration in the tumor microenvironment (TME) upon cell death. As glutamine is essential for T-cell generation, CB-839 may also enhance T-cell proliferation and activation in the TME, which may lead to further killing of tumor cells.
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| Molecular Formula |
C26H25CLF3N7O3S
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|---|---|
| Exact Mass |
607.14
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| Elemental Analysis |
C, 51.36; H, 4.14; Cl, 5.83; F, 9.37; N, 16.13; O, 7.89; S, 5.27
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| CAS # |
1874231-60-3
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| Related CAS # |
Telaglenastat;1439399-58-2
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| PubChem CID |
118867525
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| Appearance |
Solid
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
41
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| Complexity |
812
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl.S1C(NC(CC2C=CC=CN=2)=O)=NN=C1CCCCC1=CC=C(N=N1)NC(CC1C=CC=C(C=1)OC(F)(F)F)=O
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| InChi Key |
NMVMURBPQFKTAX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H24F3N7O3S.ClH/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);1H
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| Chemical Name |
2-(pyridin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide hydrochloride
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| Synonyms |
CB-839 hydrochloride; 1874231-60-3; Telaglenastat (hydrochloride); Telaglenastat hydrochloride [USAN]; B33561JJ61; N-[6-[4-[5-[(2-pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-[3-(trifluoromethoxy)phenyl]acetamide;hydrochloride; Telaglenastat hydrochloride (USAN);
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
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.
 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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