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Bioorg Med Chem Lett. 2005 Jan 17;15(2):277-81.

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

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Athersys, Inc., 3201 Carnegie Ave., Cleveland, OH 44115, USA.


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.

[Indexed for MEDLINE]

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