Description
GSK2656157 is an ATP-competitive inhibitor of PERK enzyme activity with an IC50 of 0.9 nM. It is highly selective for PERK with IC50 values >100 nM against a panel of 300 kinases. GSK2656157 inhibits PERK activity in cells with an IC50 in the range of 10-30 nM as shown by inhibition of stress-induced PERK autophosphorylation, eIF2α substrate phosphorylation, together with corresponding decreases in ATF4 and CHOP proteins in multiple cell lines. Oral administration of GSK2656157 to mice shows a dose- and time-dependent pharmacodynamic response in pancreas as measured by PERK auto-phosphorylation. Twice daily dosing of GSK2656157 results in dose dependent inhibition of multiple human tumor xenografts growth in mice. Altered amino acid metabolism, decreased blood vessel density and vascular perfusion are potential mechanisms for the observed anti-tumor effect. However, despite its anti-tumor activity, given the on-target pharmacological effects of PERK inhibition on pancreatic function, development of any PERK inhibitor in human subjects would need to be cautiously pursued in cancer patients