title: Small Molecule Inhibitors of Human DNA Polymerase λ.
abstract: To discover chemical probes to further under-stand the function of individual DNA polymerases, we established a generally applicable high-throughput screening. By applying this technique we discovered three novel inhibitor classes of human DNA polymerase λ (DNA Pol λ), a key enzyme to maintain the genetic integrity of the genome. The rhodanines, classified as an excellent drug scaffold, were found to be the most potent inhibitors for DNA Pol λ. Importantly, they are up to 10 times less active against the highly similar DNA polymerase β. We investigated basic structure activity relationships. Furthermore, the rhodanines showed pharmacological activity in two human cancer cell lines. So the here reported small molecules could serve as useful DNA Pol λ probes and might serve as starting point to develop novel therapeutic agents.
authors.affiliation: Departments of Chemistry and Biology, Konstanz Research School Chemical Biology, University of Konstanz, Universitätsstr. 10, 78457 Konstanz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Strittmatter
authors.forename: Bettina
authors.initials: B
authors.lastname: Bareth
authors.forename: Timo A
authors.initials: TA
authors.lastname: Immel
authors.forename: Thomas
authors.initials: T
authors.lastname: Huhn
authors.forename: Thomas U
authors.initials: TU
authors.lastname: Mayer
authors.forename: Andreas
authors.initials: A
authors.lastname: Marx
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002470:Cell Survival; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D056945:Hep G2 Cells; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D021281:Quantitative Structure-Activity Relationship; D012236:Rhodanine / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D012236:Rhodanine; C415367:DNA polymerase beta2; D019951:DNA Polymerase beta