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Alterations in normal metabolic processes are defining features of cancer. Glutamine, an abundant amino acid in the human blood, plays a critical role in regulating several biosynthetic and bioenergetic pathways that support tumour growth. Glutaminolysis is a metabolic pathway that converts glutamine into various metabolites involved in the tricarboxylic acid (TCA) cycle and generates antioxidants that are vital for tumour cell survival. As glutaminase catalyses the initial step of this metabolic pathway, it is of great significance in cancer metabolism and tumour progression. Inhibition of glutaminase and targeting of glutaminolysis have emerged as promising strategies for cancer therapy. This review explores the role of glutaminases in cancer metabolism and discusses various glutaminase inhibitors developed as potential therapies for tumour regression. [ABSTRACT FROM AUTHOR]

Glutamine‐addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co‐occurring mutations. To identify more drug‐like GLS inhibitors, we report the amides in the wing macrocycles for GLS inhibition with unique SAR analysis. Although the amidotriazoles (amides in the wing) are in general less potent than those of acylaminothiadiazole analogs (reverse amides in the wing), macrocycle 4, 5, and 7 are selected as a potent macrocyclic GLS inhibitor in both biochemical and cell viability assays. Selected molecules result in partial reduction in intracellular glutamate levels in LR (LDK378‐resistant) cells which is consistent to their cells viability result. Finally, selected compounds reduce the growth of A549 and H460 cells which have co‐occurring mutations including KRAS and KEAP1. The putative binding mode of macrocycle 4 is also suggested using a molecular docking model. [ABSTRACT FROM AUTHOR]