To develop novel GLS1 inhibitors as effective therapeutic agents for triple-negative breast cancer (TNBC), 25 derivatives were synthesized from the natural inhibitor withangulatin A (IC₅₀ = 18.2 μM). Bioassay optimization identified a novel and selective GLS1 inhibitor 7 (IC₅₀ = 1.08 μM). In MDA-MB-231 cells, 7 diminished cellular glutamate levels by blocking glutaminolysis pathway, further triggering the generation of reactive oxygen species to induce caspase-dependent apoptosis. Molecular docking indicated that 7 interacted with a new reacting site of allosteric binding pocket by forming various interactions in GLS1. The intraperitoneal administration of 7 at a dose of 50 mg/kg exhibited remarkable therapeutic effects and no apparent toxicity in the MDA-MB-231 xenograft model, indicating its potential as a novel GLS1 inhibitor for treatment of TNBC.

为了开发新型的GLS1抑制剂作为三阴性乳腺癌（TNBC）的有效治疗剂，从天然抑制剂withangulatin A合成了25种衍生物（IC ₅₀ = 18.2μM ）。生物测定优化确定了一种新型的选择性GLS1抑制剂7（IC ₅₀ = 1.08μM ）。在MDA-MB-231细胞中，7通过阻断谷氨酰胺分解途径降低了细胞谷氨酸水平，进一步触发了活性氧的产生，从而诱导caspase依赖性细胞凋亡。分子对接表明7通过在GLS1中形成各种相互作用而与变构结合口袋的新反应位点相互作用。腹膜内给药7 在MDA-MB-231异种移植模型中，以50 mg / kg的剂量给药显示出显着的治疗效果且无明显毒性，表明其作为新型GLS1抑制剂可用于治疗TNBC。