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 re-program conventional metabolic pathways to favor their own nutritional needs and thereby confer a survival advantage. One pathway exploited towards this goal is the increase in consumption and metabolism of glutamine, termed glutaminolysis, which feeds the tricarboxylatic acid (TCA) pathway. The first step in this process is the hydrolysis of glutamine to glutamate by the amidohydrolase enzyme glutaminase 1. As such, a glutaminase 1 (GLS1) inhibitor could potentially target certain cancers by blocking the tumor cell’s ability to produce nutrients derived from glutamine. Starting from the known GLS1 inhibitor BPTES, 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 re...