Discovery of novel glutaminase 1 allosteric inhibitor with 4-piperidinamine linker and aromatic heterocycles

Glutaminase 1 (GLS1) is overexpressed in multiple types of malignant tumors and is viewed as a promising target in cancer therapy. Thus, the discovery for small-molecule GLS1 inhibitors is being urgent. Based on our previous study of C147, a potent GLS1 allosteric inhibitor yet with a limited metabolic stability, a structure-based optimization was carried out, with a series of novel GLS1 allosteric inhibitors rationally designed, synthesized and biologically evaluated. Such endeavor has culminated in the identification of 41e, a promising GLS1 allosteric inhibitor with 4-piperidinamine linker and aromatic heterocycles. 41e displayed robust GLS1 binding affinity, superior liver microsome metabolic stability, and moderate anti-tumor activity (TGI: 47.5%) in HCT116 xenograft model with no considerable toxicity in vivo. The mechanism underlying the anti-proliferative effect of 41e on HCT116 cells was studied, revealing that the compound blocked the glutamine metabolism, induced the production of ROS, and triggered apoptosis. These findings merit further investigation of 41e as a targeted cancer therapeutic. [Display omitted] •A series of novel GLS1 allosteric inhibitors with 4-piperidinamine linker and aromatic heterocycles were designed.•41e displayed potent GLS1 inhibitory activity, robust GLS1 binding affinity, superior metabolic stability, and moderate antitumor activity in HCT116 xenograft model without toxicity.•41e could block the glutamine metabolism, induce the production of ROS, and trigger apoptosis.