电压依赖性阴离子选择性通道亚型 1 (VDAC1) 是细胞代谢和细胞凋亡的关键成分，在许多癌症类型中发挥着重要作用，提供了独特的治疗干预点。通过从计算机到体外的方法，我们鉴定了一组 VA 分子（VDAC 拮抗剂），它们选择性地与 VDAC1 结合并对癌细胞表现出特异性。生化表征表明，VA 分子可以通过与内源配体 NADH 竞争部分共享的结合位点，以微摩尔亲和力直接与 VDAC1 相互作用。 NADH 置换会导致线粒体窘迫和细胞增殖减少，尤其是与非癌细胞相比。对肝内胆管癌患者的类器官进行的实验表明，与吉西他滨等传统治疗相比，VA 分子治疗后细胞活力呈剂量依赖性降低，对健康细胞的影响较小。 VA 分子是化学实体，代表着通过精确的代谢干预作为癌症治疗策略进一步优化和开发的有希望的候选者。© 2024 作者。

The voltage-dependent anion-selective channel isoform 1 (VDAC1) is a pivotal component in cellular metabolism and apoptosis with a prominent role in many cancer types, offering a unique therapeutic intervention point. Through an in-silico-to-in-vitro approach we identified a set of VA molecules (VDAC Antagonists) that selectively bind to VDAC1 and display specificity toward cancer cells. Biochemical characterization showed that VA molecules can directly interact with VDAC1 with micromolar affinity by competing with the endogenous ligand NADH for a partially shared binding site. NADH displacement results in mitochondrial distress and reduced cell proliferation, especially when compared to non-cancerous cells. Experiments performed on organoids derived from intrahepatic cholangiocarcinoma patients demonstrated a dose-dependent reduction in cell viability upon treatment with VA molecules with lower impact on healthy cells than conventional treatments like gemcitabine. VA molecules are chemical entities representing promising candidates for further optimization and development as cancer therapy strategies through precise metabolic interventions.© 2024 The Authors.