J Med Chem. 2019 Jan 10;62(1):46-59. doi: 10.1021/acs.jmedchem.8b00327. Epub 2018 Jul 3.
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.
肾型谷氨酰胺酶（GLS）是谷氨酰胺分解途径中的第一个酶，催化谷氨酰胺水解为谷氨酸。研究发现，GLS 在许多依赖谷氨酰胺的癌细胞中上调。因此，选择性抑制 GLS 作为一种针对癌症代谢的治疗方法引起了广泛关注。双-[5-（苯乙酰氨基）-1,3,4-噻二唑-2-基]乙基二硫化物（BPTES）尽管理化性质较差，但作为关键的分子模板，在随后的努力中，发现了更有效和类药性的别构 GLS 抑制剂。本文综述了迄今为止在 GLS 抑制剂开发方面取得的进展，并强调了在系统 SAR 研究指导下，将不利的先导化合物转化为“类药性”化合物的显著转变。
