upgl00004

Description: UPGL00004 is a novel and potent inhibitor of glutaminase C (GAC, kidney glutaminase isoform C) with an IC50 of 29 nM, and it diaplays high selectivity for GAC over GLS2. UPGL00004 is able to inhibit the enzymatic activity of GAC and the growth of the triple negative MDA-MB-231 breast cancer cells with low nanomolar potency. UPGL00004 and analogs has a reduced number of rotatable bonds, improved ClogPs, microsomal stability and ligand efficiency when compared to the leading GAC inhibitors BPTES and CB-839. Property improvements were achieved by the replacement of the flexible n-diethylthio or the n-butyl moiety present in the leading inhibitors by heteroatom substituted heterocycloalkanes. Altered glycolytic flux in cancer cells (the 'Warburg effect') causes their proliferation to rely upon elevated glutamine metabolism ('glutamine addiction'). This requirement is met by the overexpression of glutaminase C (GAC), which catalyzes the first step in glutamine metabolism and therefore represents a potential therapeutic target.

References: Bioorg Med Chem. 2016 Apr 15; 24(8):1819-39; J Biol Chem. 2018 Mar 9; 293(10):3535-3545.