The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.

中文翻译：

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对 ASCT2 依赖性谷氨酰胺转运的药理学阻断可在临床前模型中产生抗肿瘤功效。

癌细胞独特的代谢需求凸显了精准医学时代药物发现的潜在丰硕机会。然而，迄今为止，以癌症代谢为治疗目标的新药却少之又少。中性氨基酸谷氨酰胺是癌细胞利用的众多代谢过程中的关键中间体，包括生物合成、细胞信号传导和氧化保护。在此，我们报告了 V-9302 的临床前开发，V-9302 是一种跨膜谷氨酰胺通量的竞争性小分子拮抗剂，选择性且有效地靶向氨基酸转运蛋白 ASCT2。V-9302 对 ASCT2 的药理学阻断导致癌细胞生长和增殖减弱、细胞死亡增加和氧化应激增加，这些共同促进了体外和体内的抗肿瘤反应。据我们所知，这是第一项证明谷氨酰胺转运药理学抑制剂在肿瘤学中的效用的研究，代表了一类新的靶向治疗，并为针对癌细胞代谢的范式转变疗法奠定了框架。