CB-839

CB-839 is a potent and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC), and with IC50s of 23 nM and 28 nM in kidney and brain, respectively.

In Vitro:CB-839 has increased potency and distinct kinetic behavior, exhibiting a slow-on/slow-off mechanism. CB-839 has a potent effect on the proliferation of HCC1806 and MDA-MB-231 cell lines (IC50 of 20-55 nM associated with cell loss at >100 nM). TNBC cell lines are sensitive to glutaminase inhibition with CB-839[1].

In Vivo:CB-839 (200 mg/kg, p.o.) has antitumor activity in xenograft models of TNBC and basal-like breast cancer, and inhibits tumor glutaminase activity and changes metabolite levels[1].

References:
[1]. Gross MI, et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014 Apr;13(4):890-901. [2]. Reisz JA, et al. Red blood cells in hemorrhagic shock: a critical role for glutaminolysis in fueling alanine transamination in rats. Blood Adv. 2017 Jul 14;1(17):1296-1305. [3]. Gregory MA, et al. Glutaminase inhibition improves FLT3 inhibitor therapy for acute myeloid leukemia. Exp Hematol. 2018 Feb;58:52-58.

Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer.[Pubmed:24523301]

Mol Cancer Ther. 2014 Apr;13(4):890-901.

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.

Telaglenastat (CB-839) is a first-in-class, selective, reversible and orally active glutaminase 1 (GLS1) inhibitor. Telaglenastat selectively inhibits GLS1 splice variants KGA (kidney-type glutaminase) and GAC (glutaminase C) compared to GLS2. The IC50s are 23 nM and 28 nM for endogenous glutaminase in mouse kidney and brain, respectively. Telaglenastat inudces autophagy and has antitumor activity.

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