Novel allosteric glutaminase inhibitors with macrocyclic structure activity relationship analysis (part 2)

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.