2. Academic Validation
  3. 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
PMID: 15603939 DOI: 10.1016/j.bmcl.2004.10.086
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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