Discovery of a Thiadiazole–Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models

Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell’s ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)­ethyl sulfide, we describe the medicinal chemistry evolution of a series from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic properties to cell potent examples with reduced molecular weight and lipophilicity, leading to compounds with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.肿瘤已演化出多种重编程常规代谢通路的方式，以满足自身营养需求，其中包括谷氨酰胺分解（glutaminolysis），该过程的第一步是由酰胺水解酶谷氨酰胺酶1（glutaminase 1, GLS1）将谷氨酰胺水解为谷氨酸。谷氨酰胺酶1抑制剂可通过阻断肿瘤细胞生成谷氨酰胺衍生营养物质的能力，实现对特定癌症的靶向治疗。本研究以已知GLS1抑制剂双-2-(5-苯乙酰胺基-1,2,4-噻二唑-2-基)乙基硫醚（bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide）为起点，阐述了一系列化合物的药物化学演化路径：从理化性质与药代动力学特性欠佳的亲脂性抑制剂，优化得到分子量与亲脂性均降低且细胞活性优异的衍生物，最终获得口服暴露量大幅提升的化合物，这类化合物可在体内实现靶点结合，并在相关疾病模型中展现出治疗活性。