Author/Authors :
L. Nathan Tumey، نويسنده , , David Bom، نويسنده , , Bayard Huck، نويسنده , , Elizabeth Gleason، نويسنده , , Jianmin Wang، نويسنده , , Daniel Silver، نويسنده , , Kurt Brunden، نويسنده , , Sherry Boozer، نويسنده , , Stephen Rundlett، نويسنده , , Bruce Sherf، نويسنده , , Steven Murphy، نويسنده , , Tom Dent، نويسنده , , Christina Leventhal، نويسنده , , Andrew Bailey، نويسنده , , John Harrington، نويسنده , , Youssef L. Bennani، نويسنده ,
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.
Keywords :
FEN1 , Endonuclease , DNA repair , cancer
