The identification and optimization of a N-hydroxy urea series of flap endonuclease 1 inhibitors.
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.
Tumey
L Nathan
LN
Athersys, Inc., 3201 Carnegie Ave., Cleveland, OH 44115, USA. ntumey@athersys.com
Bom
David
D
Huck
Bayard
B
Gleason
Elizabeth
E
Wang
Jianmin
J
Silver
Daniel
D
Brunden
Kurt
K
Boozer
Sherry
S
Rundlett
Stephen
S
Sherf
Bruce
B
Murphy
Steven
S
Dent
Tom
T
Leventhal
Christina
C
Bailey
Andrew
A
Harrington
John
J
Bennani
Youssef L
YL
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
D004791:Enzyme Inhibitors; D003606:Dacarbazine; D014508:Urea; D008741:Methyl Methanesulfonate; D045585:Flap Endonucleases; D000077204:Temozolomide