GSK864

This small molecule and its inactive analog, GSK990, are early-stage probe candidates for studying the inhibition of mutant IDH1 in cancer. Further biochemical profiling needs to be completed to better understand the other intracellular targets of GSK864.

The selectivity of GSK864 for IDH1 was illustrated by conducting a chemoproteomics experiment with a closely related analog, GSK321 [PMID: 26436839]. GSK321 was functionalized so that it could be immobilized to NHS-activated sepharose beads, which were then incubated with a lysate (protein concentration 5 mg/mL) from HT-1080 cells. The experimental plan included using GSK990 and vehicle as control bait. The proteins were eluted from the beads and then subjected to in-gel digestion and labelling with TMT reagents. LC/MS/MS identified over 300 proteins of which only one, IDH1 had IC₅₀ < 200 nM. 

GSK864 is an allosteric inhibitor of mutant IDH1, with moderate selectivity versus wild-type IDH1 and IDH2. GSK864 dose-dependently reduces levels of intracellular levels of 2-HG both in vitro and in vivo in a xenograft model. The binding mode of an analog, GSK321, bound to mutant IDH1 was determined by crystallographically, revealing that it binds an allosteric site. GSK321 appears to lock the enzyme in an inactive conformation.