title: Irreversible inhibition of DNA polymerase β by small-molecule mimics of a DNA lesion.
abstract: Abasic sites are ubiquitous DNA lesions that are mutagenic and cytotoxic but are removed by the base excision repair pathway. DNA polymerase β carries out two of the four steps during base excision repair, including a lyase reaction that removes the abasic site from DNA following incision of its 5'-phosphate. DNA polymerase β is overexpressed in cancer cells and is a potential anticancer target. Recently, DNA oxidized abasic sites that are produced by potent antitumor agents were shown to inactivate DNA polymerase β. A library of small molecules whose structures were inspired by the oxidized abasic sites was synthesized and screened for the ability to irreversibly inhibit DNA polymerase β. One candidate (3a) was examined more thoroughly, and modification of its phosphate backbone led to a molecule that irreversibly inactivates DNA polymerase β in solution (IC50 ≈ 21 μM), and inhibits the enzyme's lyase activity in cell lysates. A bisacetate analogue is converted in cell lysates to 3a. The bisacetate is more effective in cell lysates, more cytotoxic in prostate cancer cells than 3a and potentiates the cytotoxicity of methyl methanesulfonate between 2- and 5-fold. This is the first example of an irreversible inhibitor of the lyase activity of DNA polymerase β that works synergistically with a DNA damaging agent.
authors: Department of Chemistry, Johns Hopkins University , 3400 North Charles Street, Baltimore, Maryland 21218, United States.
authors: Dumitru
authors: D
authors: Arian
authors: Mohammad
authors: M
authors: Hedayati
authors: Haoming
authors: H
authors: Zhou
authors: Zoe
authors: Z
authors: Bilis
authors: Karen
authors: K
authors: Chen
authors: Theodore L
authors: TL
authors: DeWeese
authors: Marc M
authors: MM
authors: Greenberg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000502:physiology*; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011471:Prostatic Neoplasms / Q000188:drug therapy*
chemical_list: D004791:Enzyme Inhibitors; D019951:DNA Polymerase beta