From a Natural Product Lead to the Identification of Potent and Selective Benzofuran-3-yl-(indol-3-yl)maleimides as Glycogen Synthase Kinase 3β Inhibitors That Suppress Proliferation and Survival of Pancreatic Cancer Cells

Recent studies have demonstrated that glycogen synthase kinase 3 beta (GSK-3 beta) is overexpressed in human colon and pancreatic carcinomas, contributing to cancer cell proliferation and survival. Here, we report the design, synthesis, and biological evaluation of benzofuran-3-yl-(indol-3-yl)maleimides, potent GSK-3 beta inhibitors. Some of these compounds show picomolar inhibitory activity toward GSK-3 beta and an enhanced selectivity against cycl in-dependent kinase 2 (CDK-2). Selected GSK-3 beta inhibitors were tested in the pancreatic cancer cell lines MiaPaCa-2, BXPC-3, and HupT3. We determined that some of these compounds, namely compounds 5, 6, 11, 20, and 26, demonstrate antiproliferative activity against some or all of the pancreatic cancer cells at low micromolar to nanomolar concentrations. We found that the treatment of pancreatic cancer cells with GSK-3 beta inhibitors 5 and 26 resulted in suppression of GSK-3 beta activity and a distinct decrease of the X-linked inhibitor of apoptosis (XIAP) expression, leading to significant apoptosis. The present data suggest a possible role for GSK-3 beta inhibitors in cancer therapy, in addition to their more prominent applications in CNS disorders.