N-Aroyl indole thiobarbituric acids as inhibitors of DNA repair and replication stress response polymerases.

ABSTRACT: Using a robust and quantitative assay, we have identified a novel class of DNA polymerase inhibitors that exhibits some specificity against an enzyme involved in resistance to anti-cancer drugs, namely, human DNA polymerase eta (hpol η). In our initial screen, we identified the indole thiobarbituric acid (ITBA) derivative 5-((1-(2-bromobenzoyl)-5-chloro-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (ITBA-12) as an inhibitor of the Y-family DNA member hpol η, an enzyme that has been associated with increased resistance to cisplatin and doxorubicin treatments. An additional seven DNA polymerases from different subfamilies were tested for inhibition by ITBA-12. Hpol η was the most potently inhibited enzyme (30 ± 3 μM), with hpol β, hpol γ, and hpol κ exhibiting comparabl

SUBMITTER: Coggins GE 

PROVIDER: S-EPMC3746001 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature