Biological Activity

Bioactivity / Mechanism

Telaglenastat (CB-839) inhibits glutaminase C (GAC) through an allosteric binding site associated with the activation loop and distinct from the catalytic site. In a recombinant GAC assay initiated without prolonged drug preincubation, its reported mean IC50 was 180 nM; potency depends on assay conditions. [1]

Literature-reported observations and conditions; not Adooq-tested protocols or general treatment recommendations.

Target & Activity

Target	Activity	Value
glutaminase		24 nM

Cellular Effect

Cell Line	Activity	Value	Description	Reference
A549	IC50	0.026 μM	Antiproliferative activity against human A549 cells incubated for 72 hrs by Celltiter-Glo assay	[PMID: 36038117]
A549	IC50	0.04 μM	Antiproliferative activity against human A549 cells after 5 days by EZMTT reagent-based assay	[PMID: 30543285]
A549	IC50	6 nM	Antiproliferative activity against human A549 cells assessed as reduction in cell viability measured after 72 hrs by celltiter-fluor assay	[PMID: 33118821]
CAKI-1	IC50	0.04 μM	Antiproliferative activity against human Caki1 cells after 5 days by EZMTT reagent-based assay	[PMID: 30543285]
CT26	IC50	0.42 μM	Antiproliferative activity against mouse CT26 cells overexpressing GLS1 assessed as inhibition of cell proliferation measured after 72 hrs by MTT assay	[PMID: 35428013]
H22	IC50	> 10 μM	Antiproliferative activity against mouse H22 cells after 5 days by EZMTT reagent-based assay	[PMID: 30543285]
H22	IC50	1.34 μM	Antiproliferative activity against mouse H22 cells assessed as inhibition of cell proliferation measured after 72 hrs by MTT assay	[PMID: 35428013]
HCC1806	IC50	100 nM	Anticancer activity against human HCC1806 cells assessed as cell growth inhibition incubated for 72 hrs by CellTiter-Blue assay	[PMID: 33650861]
HCC827	IC50	51.42 μM	Cytotoxicity against human erlotinib-resistant HCC827 cells assessed as growth inhibition after 48 hrs by CCK8 assay	[PMID: 28174105]
HCT-116	IC50	0.028 μM	Antiproliferative activity against human HCT116 cells after 5 days by EZMTT reagent-based assay	[PMID: 30543285]
HCT-116	IC50	0.06 μM	Antiproliferative activity against human HCT-116 cells overexpressing GLS1 assessed as inhibition of cell proliferation measured after 72 hrs by MTT assay	[PMID: 35428013]
HCT-116	IC50	0.06 μM	Antiproliferative activity against human HCT116 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay	[PMID: 31603674]
HCT-116	IC50	0.11 μM	Antiproliferative activity against human HCT116 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay	[PMID: 33792311]
HT-1080	IC50	44.38 μM	Cytotoxicity against human HT1080 cells assessed as growth inhibition after 48 hrs by CCK8 assay	[PMID: 28174105]
MDA-MB-231	IC50	33 nM	Cytotoxicity against human MDA-MB-231 cells measured on 6th day by hemocytometry	[PMID: 26988803]
MDA-MB-231	IC50	50 nM	Anticancer activity against human MDA-MB-231 cells assessed as cell growth inhibition incubated for 72 hrs by CellTiter-Blue assay	[PMID: 33650861]
MDA-MB-436	IC50	0.41 μM	Antiproliferative activity against human MDA-MB-436 cells overexpressing GLS1 assessed as inhibition of cell proliferation measured after 72 hrs by MTT assay	[PMID: 35428013]
MDA-MB-436	IC50	0.43 μM	Antiproliferative activity against human MDA-MB-436 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay	[PMID: 33792311]
MDA-MB-436	IC50	0.52 μM	Antiproliferative activity against human MDA-MB-436 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay	[PMID: 31603674]

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In Vitro

Telaglenastat (CB-839) exhibits potent, time-dependent, and slowly reversible inhibition of glutaminase activity in vitro. Biochemical assays using recombinant human glutaminase C (rHu-GAC) demonstrate that preincubation with CB-839 for 1 hour results in subnanomolar to low-nanomolar IC₅₀ values (<50 nM), which are at least 13-fold lower than those observed with the earlier-generation inhibitor BPTES [1]. These enzyme kinetics suggest a tight-binding, noncompetitive mode of inhibition that effectively blocks the conversion of glutamine to glutamate in glutaminolysis-dependent cancer cells.

In cellular assays, CB-839 shows marked antiproliferative activity in glutamine-addicted tumor cell lines. For instance, in triple-negative breast cancer (TNBC) cell lines such as HCC-1806 and MDA-MB-231, CB-839 significantly reduces cell viability in a dose-dependent manner, with IC₅₀ values in the low micromolar range. In contrast, CB-839 has minimal effect on estrogen receptor–positive (ER⁺) breast cancer cell lines like T47D, which exhibit lower dependence on glutamine metabolism [1,2].

Metabolic flux analysis using [U-¹³C]-glutamine tracers further confirms that CB-839 treatment reduces incorporation of glutamine-derived carbon into downstream TCA cycle intermediates such as α-ketoglutarate, succinate, and malate [3]. This inhibition of glutaminolysis leads to reduced ATP production and increased oxidative stress, ultimately triggering growth arrest or apoptosis depending on the cellular context.

Additionally, CB-839 has shown selective cytotoxicity in AML (acute myeloid leukemia) cell lines and primary AML blasts, but not in normal hematopoietic stem/progenitor cells (HSPCs), suggesting a favorable therapeutic window [4]. These in vitro findings support the rationale for targeting glutaminase in glutamine-addicted tumors.

In Vitro Studies

In H460 lung tumor cells, 24-hour pretreatment with 1 μM CB-839 increased the clonogenic response to subsequent 4 or 8 Gy irradiation relative to vehicle controls. These results describe a radiation combination under defined culture conditions. [2]

Assay-dependent inhibition of recombinant GAC

Biochemical assay · Purified recombinant human GAC (50 nM), phosphate-stimulated activity [1]

Without the 4-hour preincubation used in the earlier report, the authors measured a mean CB-839 IC50 of 180 nM. This is an enzyme-assay endpoint, not a cell-treatment concentration or universal potency.

Measured endpoints — not treatment concentrations
Endpoint	Reported result	Reference
Inhibition of recombinant GAC catalytic activity	IC50 mean 180 nM	[1]

Literature-Reported Treatment Conditions

Treatment concentration: Various inhibitor concentrations; 20 mM glutamine; 150 mM potassium phosphate
Exposure duration: 10-minute GAC reaction at room temperature; immediately initiated without drug preincubation
Method: Two-step glutamate dehydrogenase-coupled absorbance assay at 340 nm; triplicate experiments; four-parameter logistic fit
Vehicle: 2% DMSO
Reported limits: CB-839 titration range and uncertainty around its reported mean IC50 are not provided in the selected result paragraph.

Methods and source locations

Compound reported in the paper: Telaglenastat (CB-839); Compound label in the paper: CB-839

Named parent compound evidence; no validation of Adooq SKU, batch purity, formulation equivalence or clinical efficacy.

Results: comparison of inhibition; Experimental procedures: Glutaminase activity assays

Inhibition of recombinant GAC catalytic activity: Immediate phosphate initiation; no 4-hour preincubation; coupled enzymatic assay — Results, first paragraph comparing recombinant GAC inhibition; Glutaminase activity assays

Structural basis for allosteric GAC binding

Biochemical assay · Mature human GAC (residues 73–598) complexed with CB-839; PDB 5HL1 [1]

The CB-839–GAC crystal structure locates the inhibitor in the activation-loop-associated pocket at the subunit interface, away from the catalytic site, supporting an allosteric mechanism. Terminal aromatic groups are less well resolved than the inhibitor core.

Measured endpoints — not treatment concentrations
Endpoint	Reported result	Reference
CB-839–GAC diffraction structure	Resolution 2.4 Å	[1]
Binding-site position relative to catalytic site	Qualitative structural observation Activation-loop-associated intersubunit pocket distinct from the catalytic site	[1]

Literature-Reported Treatment Conditions

Treatment concentration: Protein:inhibitor mole ratio 1:4
Exposure duration: Complex incubated on ice for 1 hour before crystal growth
Method: X-ray crystallography; molecular replacement using unliganded GAC; comparison with BPTES and UPGL00004 complexes
Vehicle: Inhibitor stock in DMSO
Reported limits: Structural binding does not establish cellular exposure or a clinical dose.

Methods and source locations

Compound reported in the paper: Telaglenastat (CB-839); Compound label in the paper: CB-839

Named parent compound evidence; no validation of Adooq SKU, batch purity, formulation equivalence or clinical efficacy.

Results: Comparison of the X-ray structures; Figure 4B versus 4C–D; Table 2; Crystallization of GAC and CB-839 or UPGL00004

CB-839–GAC diffraction structure: X-ray crystallography; PDB 5HL1 — Table 2, GAC/CB-839 column; Figure 4B caption

Binding-site position relative to catalytic site: Co-crystal structure and comparison with inhibitor-bound and free GAC — Results: comparison of structures; Figure 4B–D and caption

CB-839 pretreatment increases H460 radiation response

Cell-based study · H460 human lung tumor cells; clonogenic survival after irradiation [2]

CB-839 pretreatment reduced clonogenic survival after 4 or 8 Gy relative to medium/vehicle controls. The response resembled glutamine withdrawal under the same assay conditions.

Measured endpoints — not treatment concentrations
Endpoint	Reported result	Reference
Clonogenic survival after radiation with CB-839 pretreatment	Qualitative dose-response comparison Lower surviving fraction with CB-839 than vehicle at 4 and 8 Gy; mean ± SD of three independent experiments	[2]

Literature-Reported Treatment Conditions

Treatment concentration: 1 μM CB-839
Exposure duration: 24-hour pretreatment, followed by irradiation; colonies allowed to grow for at least six doubling times (~8 days)
Method: Clonogenic assay after single 4 or 8 Gy X-ray exposure
Vehicle: 1% DMSO in all drug/vehicle treatments
Co-treatment: Single 4 or 8 Gy radiation exposure
Reported limits: No exact surviving fractions or statistical synergy metric extracted from the curves.

Methods and source locations

Compound reported in the paper: Telaglenastat (CB-839); Compound label in the paper: CB-839

Named parent compound evidence; no validation of Adooq SKU, batch purity, formulation equivalence or clinical efficacy.

Material and Methods: Colony Forming Assay; Results and Discussion, H460 radiation response; Figure 2B and caption

Clonogenic survival after radiation with CB-839 pretreatment: Colony formation; medium, DMSO vehicle and glutamine-free medium comparator conditions — Figure 2B and caption; Colony Forming Assay; Results paragraph on H460

In Vivo Studies

In female nude mice bearing H460 xenografts, three oral doses of CB-839 (200 mg/kg per dose) before a single 12 Gy exposure increased tumor growth delay relative to radiation alone. The same short CB-839 regimen alone did not inhibit tumor growth. The study used five female mice per plotted group. [2]

Short-course CB-839 with radiation in H460 xenografts

Animal study · Female nude mice bearing subcutaneous H460 lung-tumor xenografts; five mice per plotted group [2]

Three CB-839 doses before a single 12 Gy exposure increased tumor growth delay relative to radiation alone. CB-839 alone under this short schedule did not inhibit tumor growth. This is a combination result in an ectopic immunodeficient model.

Measured endpoints — not treatment concentrations
Endpoint	Reported result	Reference
Relative tumor growth after CB-839 with or without radiation	Qualitative growth-delay comparison Combination delayed growth more than 12 Gy alone; three-dose CB-839 monotherapy did not inhibit growth; n=5 female mice/group, mean and SD	[2]

Study groups and reported outcomes
Group / dose	Comparator	Observed result	Reference
Untreated control	Baseline without CB-839 or radiation	Tumor growth reference	[2]
CB-839 alone 200 mg/kg per dose	Compared with untreated control	Short three-dose CB-839 regimen did not inhibit tumor growth	[2]
12 Gy alone	Compared with untreated control	Slower relative tumor growth than untreated control	[2]
CB-839 plus 12 Gy 200 mg/kg per dose	Single 12 Gy radiation exposure; compared with radiation alone and single-agent CB-839	Combination produced greater tumor growth delay than radiation alone	[2]

Untreated control: Model: Female nude mice bearing subcutaneous H460 xenografts; Treatment course: Single radiation exposure or untreated control; Figure 3B follow-up through day 20; Reported limits: Animal formulation/vehicle composition is not reported in the read main manuscript methods.

CB-839 alone: Model: Female nude mice bearing subcutaneous H460 xenografts; Route: Oral gavage; Frequency: Three doses, 28, 16 and 4 hours before irradiation; Treatment course: Three-dose CB-839 pretreatment; Figure 3B follows relative tumor growth through day 20; Reported limits: Animal formulation/vehicle composition is not reported in the read main manuscript methods.

12 Gy alone: Model: Female nude mice bearing subcutaneous H460 xenografts; Treatment course: Single radiation exposure or untreated control; Figure 3B follow-up through day 20; Reported limits: Animal formulation/vehicle composition is not reported in the read main manuscript methods.

CB-839 plus 12 Gy: Model: Female nude mice bearing subcutaneous H460 xenografts; Route: Oral gavage; Frequency: Three doses, 28, 16 and 4 hours before irradiation; Treatment course: Three-dose CB-839 pretreatment; Figure 3B follows relative tumor growth through day 20; Reported limits: Animal formulation/vehicle composition is not reported in the read main manuscript methods.

Methods and source locations

Compound reported in the paper: Telaglenastat (CB-839); Compound label in the paper: CB-839

Named parent compound evidence; no validation of Adooq SKU, batch purity, formulation equivalence or clinical efficacy.

Human Xenografts Model in Mouse; Figure 3B and caption; Results and Discussion including limitations

Relative tumor growth after CB-839 with or without radiation: Caliper measurements; four conditions plotted — Figure 3B and caption; Results and Discussion

Untreated control · Human Xenografts Model in Mouse; Figure 3B and caption; Results and Discussion

CB-839 alone · Human Xenografts Model in Mouse; Figure 3B and caption; Results and Discussion

12 Gy alone · Human Xenografts Model in Mouse; Figure 3B and caption; Results and Discussion

CB-839 plus 12 Gy · Human Xenografts Model in Mouse; Figure 3B and caption; Results and Discussion

Specifications

Manufacturer	Adooq Bioscience
Actions	Inhibitor
CAS Number	1439399-58-2
Applications	Glutaminase inhibitor
Formula	C₂₆H₂₄F₃N₇O₃S
Molecular Weight	571.57
Synonyms	CB839
SMILES	O=C(CC1=CC=CC(OC(F)(F)F)=C1)NC2=CC=C(CCCCC3=NN=C(NC(CC4=NC=CC=C4)=O)S3)N=N2

Storage & Solubility

In Vitro Solubility

Reported Solubility

Solvent	Reported Solubility
DMSO	Warmed: 97 mg/mL (169.7 mM)
Water	Insoluble
Ethanol	Insoluble

Preparing Stock Solutions

Stock preparation is unavailable for this product molecular weight.

Calculated stock concentrations do not establish solvent solubility. Refer to the reported solubility data for experimental guidance.

In Vivo Preparation

Concentration: 2 mg/mL
Vehicle: 5% DMSO+corn oil

Storage

Store powder at -20°C, keep desiccated.
In powder form, the chemical is stable for 36 months.
In solution, store at -20°C and use within 1 month to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles.

Research References

[1] Huang Q, Stalnecker C, Zhang C, et al. Characterization of the interactions of potent allosteric inhibitors with glutaminase C, a key enzyme in cancer cell glutamine metabolism. The Journal of biological chemistry (2018). PMID: 29317493 DOI: 10.1074/jbc.m117.810101 Source material
[2] Boysen G, Jamshidi-Parsian A, Davis MA, et al. Glutaminase inhibitor CB-839 increases radiation sensitivity of lung tumor cells and human lung tumor xenografts in mice. International journal of radiation biology (2019). PMID: 30557074 DOI: 10.1080/09553002.2018.1558299 Source material

Publications

1 publication citing this product

Beatriz Giesen, .et al. , Pharmaceutics, 2021, Feb 23;13(2):295 PMID: 33672398

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Telaglenastat (CB-839)

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Biological Activity

Bioactivity / Mechanism

Target & Activity

Cellular Effect

In Vitro

In Vitro Studies

Assay-dependent inhibition of recombinant GAC

Literature-Reported Treatment Conditions

Structural basis for allosteric GAC binding

Literature-Reported Treatment Conditions

CB-839 pretreatment increases H460 radiation response

Literature-Reported Treatment Conditions

In Vivo Studies

Short-course CB-839 with radiation in H460 xenografts

Specifications

Storage & Solubility

In Vitro Solubility

Reported Solubility

Preparing Stock Solutions

In Vivo Preparation

Storage

Research References

Publications

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