Discovery of aminothiazole derivatives as a chemical scaffold for glutaminase inhibition

Abstract

Cancer cells rely on different mechanisms to maintain their dysregulated metabolism and high proliferation. Metabolic rewiring with an increased dependency on glutamine, the most abundant amino acid in the blood, is a common feature of several types of cancers, including triple-negative breast cancer (TNBC). The enzyme glutaminase (GLS) converts glutamine to glutamate, a reaction that provides α-ketoglutarate for the tricarboxylic/citric acid cycle (TCA) and chromatin-modifying enzymes, thus impacting proliferation and cell differentiation. Glutamine metabolism also impacts the redox balance and synthesis of nucleotides, lipids, and other amino acids. Glutaminase is a potential therapeutic target for cancer, with inhibitors in clinical trials. We previously performed high-throughput screening (HTS) to look for GLS inhibitors. Here, we present the structure–activity relationship (SAR) study of one of the hits, C12, a molecule containing the heteroaromatic nucleus 2-amino-thiazole. The SAR investigation was carried out through modifications of the substituents from the main 3 rings present at the C12 prototype, rings A-C. The combination of 4-F and phenylacetic substitutions on ring A, the incorporation of a 1,3,4-thiadiazole moiety on ring B, and a 4-CN substituent on ring C were the best options to improve specific GLS inhibition. In this series, three compounds exhibited suitable enzyme (GAC vs GLS2) and cell (MDA-MB-231 vs SKBR3) selectivity and, thus, could be useful for the development of new glutaminase inhibitors.

Keywords

• Triple-negative breast cancer
• Glutaminase
• Cell metabolism
• High throughput screening
• Enzyme inhibitors