Kidney-type glutaminase (GLS), the first enzyme in the glutaminolysis pathway, catalyzes the hydrolysis of glutamine to glutamate. GLS was found to be upregulated in many glutamine-dependent cancer cells. Therefore, selective inhibition of GLS has gained substantial interest as a therapeutic approach targeting cancer metabolism. Bis-2-[5-(phenylacetamido)-1,3,4-thiadiazol-2-yl]ethyl sulfide (BPTES), despite its poor physicochemical properties, has served as a key molecular template in subsequent efforts to identify more potent and drug-like allosteric GLS inhibitors. This review article provides an overview of the progress made to date in the development of GLS inhibitors and highlights the remarkable transformation of the unfavorable lead into “druglike” compounds guided by systematic SAR studies.

中文翻译：

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肾型谷氨酰胺酶变构抑制剂发现的新进展

肾型谷氨酰胺酶 (GLS) 是谷氨酰胺分解途径中的第一种酶，它催化谷氨酰胺水解为谷氨酸。发现 GLS 在许多谷氨酰胺依赖性癌细胞中上调。因此，选择性抑制 GLS 作为一种靶向癌症代谢的治疗方法已经引起了人们的极大兴趣。Bis-2-[5-(phenylacetamido)-1,3,4-thiadiazol-2-yl]ethyl sulfide (BPTES) 尽管其物理化学性质较差，但在随后的努力中已作为关键分子模板来鉴定更有效和更有效的物质。药物样变构 GLS 抑制剂。这篇综述文章概述了迄今为止在 GLS 抑制剂开发方面取得的进展，并强调了在系统 SAR 研究的指导下，不利的铅显着转变为“类药物”化合物。