Abstract: Telaglenastat (CB-839) is a first-in-class, orally bioavailable, selective, and noncompetitive small molecule inhibitor of glutaminase (GLS). By blocking the conversion of glutamine to glutamate, CB-839 disrupts the tricarboxylic acid (TCA) cycle and starves cancer cells of essential metabolic substrates. In the context of hematological malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), CB-839 has demonstrated significant preclinical and clinical potential, particularly in tumors harboring isocitrate dehydrogenase (IDH) mutations. This review explores the pharmacological activity, molecular mechanism of action, and structure-activity relationship of CB-839. Furthermore, it discusses current limitations, such as the lack of single-agent efficacy and the emergence of metabolic resistance, alongside future perspectives focusing on rational combination therapies with hypomethylating agents, ROS-inducing drugs, and immunotherapies.
1. Introduction
Metabolic reprogramming is a fundamental hallmark of cancer, enabling tumor cells to sustain rapid proliferation and survival under stress [40]. Glutamine, the most abundant circulating amino acid in human plasma, serves as a critical nutrient source for highly proliferative tumor cells, fueling the tricarboxylic acid (TCA) cycle and supporting anabolic growth [72]. Glutaminase (GLS) is the rate-limiting enzyme in glutaminolysis, catalyzing the conversion of glutamine to glutamate [40]. In hematological malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are prevalent, leading to the accumulation of the oncometabolite D-2-hydroxyglutarate (D2HG) [4]. Because glutaminase generates the main source of alpha-ketoglutarate (α-KG) in IDH-mutated cells, targeting GLS has emerged as a highly rational therapeutic strategy [4]. Telaglenastat (CB-839), developed by Calithera Biosciences, is a first-in-class, selective, and orally bioavailable GLS1 inhibitor currently under extensive clinical investigation [40][59].
2. Pharmacological Activity
CB-839 has displayed potent antiproliferative efficacy across a wide range of cancers, including leukemia, lymphoma, melanoma, breast cancer, and kidney cancer [40]. In hematological models, preclinical and in vivo studies have demonstrated that CB-839 significantly reduces the growth of IDH1/2-mutated AML cells [4]. When combined with FDA-approved leukemia drugs that induce mitochondrial reactive oxygen species (ROS), such as arsenic trioxide and homoharringtonine, CB-839 exhibits profound anti-leukemic activity [41]. Notably, this combination therapy has the potential to eradicate primary AML colony-forming cells, effectively targeting leukemia stem cells that rely heavily on enhanced mitochondrial metabolism for survival [41]. Clinically, CB-839 is being evaluated in relapsed or refractory (R/R) IDH-mutated AML patients as a monotherapy and in combination with azacitidine (NCT02071927), a standard hypomethylating agent also used extensively in MDS [4]. Beyond direct cytotoxicity, CB-839 enhances the anti-tumor activity of T-cell-mediated immunotherapies and immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1) by increasing T-cell proliferation and activation in the tumor microenvironment [15].
3. Molecular Mechanism of Action
The primary mechanism of action of CB-839 involves the selective, noncompetitive, and allosteric inhibition of GLS [40]. Specifically, CB-839 binds exclusively to the dimer interface of the GLS1 gene products (GAC and KGA isoforms), preventing the tetramerization and activation of the enzyme [40]. This binding halts the conversion of glutamine to glutamate, thereby depriving the cancer cells of a crucial carbon and nitrogen source needed for the TCA cycle and biosynthesis. In acute myeloid leukemia cells, the suppression of glutaminase by CB-839 disrupts redox homeostasis, leading to reduced intracellular glutathione (GSH) levels and a subsequent lethal increase in mitochondrial ROS, which triggers apoptosis [41]. Furthermore, by blocking glutamine consumption by tumor cells, CB-839 increases the availability of glutamine in the tumor microenvironment, which is essential for the optimal function and activation of infiltrating CD8+ T-cells [15].
4. Structure-Activity Relationship (SAR)
CB-839 was rationally designed to overcome the pharmacokinetic limitations, such as poor solubility and bioavailability, associated with earlier GLS inhibitors like BPTES [40]. Crystal structure analyses reveal that CB-839 incorporates a terminal electron-withdrawing trifluoromethoxy group [40]. This specific structural modification serves a dual purpose: it increases the integral lipophilicity of the molecule, enhancing its oral bioavailability, and it improves the electronegativity of the pyridazinyl nitrogen atoms [40]. These electronic changes result in strengthened hydrogen bond interactions at the dimer interface of the GLS enzyme, conferring CB-839 with its high potency and selectivity as a noncompetitive inhibitor [40].
5. Current Limitations
Despite its potent target inhibition, a major criticism leveled against CB-839 is its lack of robust single-agent activity in several tumor models [38]. As a monotherapy, GLS inhibition can be circumvented by tumor cells through various compensatory metabolic mechanisms [50]. To survive glutamate deprivation, resistant cells may upregulate asparagine synthetase, leading to increased asparagine concentrations that maintain amino acid uptake, mTORC1 activation, and nucleotide synthesis [51]. Additionally, resistance can be mediated by the downregulation of the glutamate/cystine antiporter (xCT) to prevent further glutamate export, or through the upregulation of pyruvate carboxylase, an enzyme that converts pyruvate into oxaloacetate to replenish the TCA cycle independently of glutamine [51].
6. Future Perspectives
To overcome the limitations of monotherapy and metabolic resistance, the future clinical development of CB-839 is heavily focused on rational combination strategies. In hematological malignancies like AML and MDS, combining CB-839 with hypomethylating agents (e.g., azacitidine) or pro-oxidant drugs (e.g., arsenic trioxide) represents a promising approach to exploit the metabolic and redox vulnerabilities of leukemia stem cells [4][41]. Furthermore, CB-839 is currently the only small molecule GLS inhibitor being evaluated in advanced clinical trials [40]. Its ability to remodel the tumor microenvironment and synergize with immune checkpoint inhibitors (such as nivolumab) or radiotherapy offers exciting new therapeutic avenues [15][47]. Ongoing and future clinical trials will be crucial in identifying the optimal combination regimens and predictive biomarkers to maximize the efficacy of Telaglenastat in patients with MDS, AML, and other glutamine-dependent cancers.
