telaglenastat (CB-839)

A selective glutaminase inhibitor, CB-839, which targets cancer cells by blocking glutamine conversion to glutamate, has shown promising preclinical results as a therapeutic target in triple-negative breast cancer treatment...Co-targeting GLS and GLS2 might be a novel approach for the treatment of this subclass. Further functional studies to evaluate the underlying molecular mechanisms of this process are warranted.

Significant synergistic effects were observed when GCLC inhibitors were combined with agents targeting the GSH synthesis pathway, specifically SLC7A11 inhibitors and the glutaminase inhibitor telaglenastat...These findings highlight the vulnerability of glutathione metabolism in SMARCB1-deficient cancers, suggesting that a GCLC inhibitor may be a promising therapeutic option. This study provides a preclinical foundation for the development of effective treatment strategies for SMARCB1-deficient cancers, including combination therapies, and supports further investigation toward future translational applications.

P2, N=42, Not yet recruiting, Washington University School of Medicine | Trial completion date: Mar 2032 --> Oct 2032 | Trial primary completion date: Mar 2032 --> Oct 2032

In A549 xenografts, LX-191 achieved 50.3% tumor growth inhibition at 10 mg/kg, outperforming CB-839 (21.6%) under identical conditions...The findings establish LX-191 as a promising flavone-based, non-BPTES lead for GLS1 inhibition, exhibiting multi-pathway antitumor activity both in vitro and in vivo. This work provides a tractable lead compound for the development of next-generation GLS1 therapeutics.

Encouragingly, agents such as the fatty acid synthase inhibitor TVB-2640 and the glutaminase inhibitor CB-839 have already entered clinical trials. We recognize that adverse effects on normal tissues and drug resistance driven by metabolic plasticity represent major challenges for metabolism-targeted therapies. Accordingly, we systematically summarize innovative strategies that offer new therapeutic possibilities, including targeting multiple metabolic pathways through combination therapy to enhance efficacy, combining metabolic inhibitors to overcome resistance to conventional anticancer agents, leveraging metabolic reprogramming for early cancer detection, and exploring emerging approaches such as immunometabolism and metabolomics.

Although allosteric GLS inhibitors such as BPTES (Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide) and later-generation analogs such as CB-839 (Telaglenastat) have pharmacologically validated this target, their clinical utility has been constrained by suboptimal drug-like properties, including poor solubility and bioavailability...This biochemical potency translated to a functional effect in a cellular model of glutamine dependence, as evidenced by a significant depletion of intracellular glutamate pools in LDK378-resistant (LR) cells. Furthermore, TRG-192 demonstrated a favorable preclinical safety profile in initial toxicological assessments. Collectively, these data-encompassing potent target engagement, functional on-target activity, and preliminary safety-provide a compelling rationale for the advancement of TRG-192 into in vivo efficacy studies.

Rational combination strategies that pair genomic-targeted agents (sotorasib and adagrasib) with metabolic inhibitors (CB-839 and TVB-2640) show promise in overcoming adaptive resistance. Integrating genomic and metabolic profiling may enhance precision oncology approaches and improve clinical outcomes.

Together, these findings establish ACTL8 as a key oncogenic driver of BC progression. Targeting ACTL8 offers a novel strategy to disrupt glutamine-dependent metabolic reprogramming, and Momordin Ic represents a promising lead agent to combat ACTL8-driven BC.

To address the limited therapeutic potential of PPE, we constructed PMC@HA nanoparticles by coencapsulating PPE within a bimetallic Cu/Zn nanocarrier and integrating the glutaminase inhibitor CB-839...When applied as a neoadjuvant regimen in conjunction with surgery, PMC@HA significantly decreases postoperative recurrence and distant metastasis in TNBC. This combinatorial approach may improve chemosensitivity and limit metastatic progression, thereby potentially extending long-term survival in patients with TNBC.

P1, N=36, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2026 --> Jun 2026 | Trial primary completion date: Jan 2026 --> Jun 2026

Combined with different clinical and pre-clinical anticancer compounds such as V9302, CB839, Sutent, Brigatinib, DRB18 significantly increased death of A549 and Panc1 cells. Mechanistically, DRB18 treatment with paclitaxel elevated the expression of Caspases 3 and 9, suggesting GLUT-inhibiting and apoptosis-inducing anticancer mechanisms of DRB18 with paclitaxel. Collectively, our results demonstrate anticancer efficacy of pan class-I GLUT inhibitor DRB18 in combination with paclitaxel, providing a potentially more efficacious therapeutic strategy for treating advanced NSCLC and other cancers.

These findings demonstrate that CB-839 exhibits significant antifibrotic effects in a rat model of liver fibrosis, primarily by modulating glutamine metabolism and key fibrotic biomarkers. CB-839 has the potential to be a promising therapeutic approach for liver fibrosis.