1. Academic Validation
  2. The identification and optimization of a N-hydroxy urea series of flap endonuclease 1 inhibitors

The identification and optimization of a N-hydroxy urea series of flap endonuclease 1 inhibitors

  • Bioorg Med Chem Lett. 2005 Jan 17;15(2):277-81. doi: 10.1016/j.bmcl.2004.10.086.
L Nathan Tumey 1 David Bom Bayard Huck Elizabeth Gleason Jianmin Wang Daniel Silver Kurt Brunden Sherry Boozer Stephen Rundlett Bruce Sherf Steven Murphy Tom Dent Christina Leventhal Andrew Bailey John Harrington Youssef L Bennani
Affiliations

Affiliation

  • 1 Athersys, Inc., 3201 Carnegie Ave., Cleveland, OH 44115, USA. ntumey@athersys.com
Abstract

FLAP endonuclease-1 (FEN1) is a key Enzyme involved in base excision repair (BER), a primary pathway utilized by mammalian cells to repair DNA damage. Sensitization to DNA damaging agents is a potential method for the improvement of the therapeutic window of traditional chemotherapeutics. In this paper, we describe the identification and SAR of a series of low nanomolar FEN1 inhibitors. Over 1000-fold specificity was achieved against a related Endonuclease, xeroderma pigmentosum G (XPG). Two compounds from this series significantly potentiate the action of methyl methanesulfonate (MMS) and temozolamide in a bladder Cancer cell line (T24). To our knowledge, these are the most potent Endonuclease inhibitors reported to date.

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