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
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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