P1, N=19, Terminated, National Cancer Institute (NCI) | N=36 --> 19 | Active, not recruiting --> Terminated; Other - Drug supply issues and withdrawal of company support.

P1, N=40, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2026 --> Sep 2026 | Trial primary completion date: May 2026 --> Sep 2026

In HNSCC xenograft models, genetic silencing of GLS1 or treatment with CB-839 markedly reduces intratumoral angiogenesis...Exosomes deficient in CAV1-TNC complexes subsequently disrupt integrin-dependent FAK-SRC signaling in endothelial cells, inhibiting their angiogenic activity. Collectively, these findings uncover a non-metabolic role of GLS1 in promoting tumor angiogenesis through exosome-mediated CAV1-TNC signaling, suggesting that targeting GLS1 may simultaneously inhibit tumor metabolism and angiogenesis in HNSCC.

P2, N=54, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2026 --> Apr 2027

Upregulation of SLC25A6 expression induced by the glutaminase inhibitor CB-839 sensitized cancer cells to the Bcl-2 inhibitor ABT-199. Our findings reveal a novel function of SLC25A6 that links metabolic stress to mitochondrial apoptosis via disruption of the MICOS complex. Combination treatments with mitochondrial apoptotic inducers represent a promising avenue for maximizing the efficacy of GMIs in cancer treatment.

P1/2, N=22, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

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.