Telaglenastat (CB-839)

CB-839 an is orally bioavailable inhibitor of glutaminase, with potential antineoplastic activity. CB-839 (Telaglenastat) also inudces autophagy and has antitumor activity.

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.

1. Gross MI, Demo SD, Dennison JB, et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014;13(4):890-901. PMID: 24548884
2. Boysen G, Jamshidi-Parsian A, Davis MA, et al. Glutaminase inhibitor CB-839 synergizes with ionizing radiation to improve response in head and neck squamous cell carcinoma models. Radiother Oncol. 2019;139:31-38. PMID: 30439663
3. Wang JB, Erickson JW, Fuji R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010;18(3):207-219. PMID: 20832749
4. Matre P, Velez J, Jacamo R, et al. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency and therapeutic strategy. Blood. 2016;128(4):534-545. PMID: 27268087