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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]

[Display omitted] Glutamine-addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co-occurring mutations. Selective glutaminase1 (GLS1) inhibition was reported using BPTES which has novel mode of allosteric inhibition. However, BPTES is a highly hydrophobic and symmetric molecule with very poor solubility which results in suboptimal pharmacokinetic parameters and hinders its further development. As an ongoing effort to identify more drug-like GLS1 inhibitors via systematic structure − activity relationship (SAR) analysis of BPTES analogs, we disclose our novel macrocycles for GLS1 inhibition with conclusive SAR analysis on the core, core linker, and wing linker, respectively. Selected molecules resulted in reduction in intracellular glutamate levels in LR (LDK378-resistant) cells which is consistent to cell viability result. Finally, compounds 13 selectively reduced the growth of A549 and H460 cells which have co-occurring mutations including KRAS and KEAP1. [ABSTRACT FROM AUTHOR]