Discovery of survivin inhibitors and beyond: FL118 as a proof of concept

Int Rev Cell Mol Biol. 2013;305:217-52. doi: 10.1016/B978-0-12-407695-2.00005-6.

Abstract

Survivin, a novel antiapoptotic protein molecule, plays a central role in cancer cell survival/proliferation networks and has therefore become a therapeutic target for cancer drug discovery efforts. There are two strategies for discovering survivin inhibitors. One is based on survivin interactions within the cell and the other strategy is based on blocking survivin expression. Survivin inhibitors developed by the first strategy would disrupt a particular survivin function. These survivin inhibitors could also be useful tools for delineating the mechanism of action of survivin. The second strategy may use a reporter system of the survivin gene to screen drug libraries. To date, two molecules, YM155 and FL118, have been identified using this strategy. These two examples provide a proof of concept that screens for inhibitors of survivin expression using survivin gene reporter assays as surrogate markers will uncover versatile small molecules that not only inhibit survivin but also inhibit other essential cancer survival/proliferation-associated targets and/or signaling pathways. This review provides an overview of current information in the area relevant to survivin inhibitors that may facilitate future studies.

Keywords: Anticancer drugs; FL118; Human cancer; Survivin inhibitors; YM155.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Benzodioxoles / chemistry
  • Benzodioxoles / pharmacology*
  • Drug Discovery*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indolizines / chemistry
  • Indolizines / pharmacology*
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Survivin

Substances

  • 7-ethyl-7-hydroxy-10H-1,3-Dioxolo(4,5-g)pyrano(3',4':6,7)indolizino(1,2-b)quinoline-8,11(7H,12H)-dione
  • BIRC5 protein, human
  • Benzodioxoles
  • Enzyme Inhibitors
  • Indolizines
  • Inhibitor of Apoptosis Proteins
  • Survivin