title: The identification and optimization of a N-hydroxy urea series of flap endonuclease 1 inhibitors.
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.
authors.affiliation: Athersys, Inc., 3201 Carnegie Ave., Cleveland, OH 44115, USA. ntumey@athersys.com
authors.forename: L Nathan
authors.initials: LN
authors.lastname: Tumey
authors.forename: David
authors.initials: D
authors.lastname: Bom
authors.forename: Bayard
authors.initials: B
authors.lastname: Huck
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gleason
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.forename: Daniel
authors.initials: D
authors.lastname: Silver
authors.forename: Kurt
authors.initials: K
authors.lastname: Brunden
authors.forename: Sherry
authors.initials: S
authors.lastname: Boozer
authors.forename: Stephen
authors.initials: S
authors.lastname: Rundlett
authors.forename: Bruce
authors.initials: B
authors.lastname: Sherf
authors.forename: Steven
authors.initials: S
authors.lastname: Murphy
authors.forename: Tom
authors.initials: T
authors.lastname: Dent
authors.forename: Christina
authors.initials: C
authors.lastname: Leventhal
authors.forename: Andrew
authors.initials: A
authors.lastname: Bailey
authors.forename: John
authors.initials: J
authors.lastname: Harrington
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D045585:Flap Endonucleases / Q000037:antagonists & inhibitors*; D006801:Humans; D008741:Methyl Methanesulfonate / Q000737:chemistry; D013329:Structure-Activity Relationship; D000077204:Temozolomide; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms; D014983:Xeroderma Pigmentosum
chemical_list: D004791:Enzyme Inhibitors; D003606:Dacarbazine; D014508:Urea; D008741:Methyl Methanesulfonate; D045585:Flap Endonucleases; D000077204:Temozolomide