From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl)maleimides as glycogen synthase kinase 3βinhibitors that suppress proliferation and survival of pancreatic cancer cells

Irina N. Gaisina, Franck Gallier, Andrei V. Ougolkov, Ki H. Kim, Toru Kurome, Songpo Guo, Denise Holzle, Doris N. Luchini, Sylvie Y. Blond, Daniel D. Billadeau, Alan P. Kozikowski

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88 Scopus citations


Recent studies have demonstrated that glycogen synthase kinase 3β (GSK-3β) 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-3β inhibitors. Some of these compounds show picomolar inhibitory activity toward GSK-3β and an enhanced selectivity against cyclin-dependent kinase 2 (CDK-2). Selected GSK-3β 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-3β inhibitors 5 and 26 resulted in suppression of GSK-3β 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-3β inhibitors in cancer therapy, in addition to their more prominent applications in CNS disorders.

Original languageEnglish (US)
Pages (from-to)1853-1863
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number7
StatePublished - Apr 9 2009


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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