title: Expanding the scope of human DNA polymerase λ and β inhibitors.
abstract: The exact biological functions of individual DNA polymerases still await clarification, and therefore appropriate reagents to probe their respective functions are required. In the present study, we report the development of a highly potent series of human DNA polymerase λ and β (pol λ and β) inhibitors based on the rhodanine scaffold. Both enzymes are involved in DNA repair and are thus considered as future drug targets. We expanded the chemical diversity of the small-molecule inhibitors arising from a high content screening and designed and synthesized 30 novel analogues. By biochemical evaluation, we discovered 23 highly active compounds against pol λ. Importantly, 10 of these small-molecules selectively inhibited pol λ and not the homologous pol β. We discovered 14 small-molecules that target pol β and found out that they are more potent than known inhibitors. We also investigated whether the discovered compounds sensitize cancer cells toward DNA-damaging reagents. Thus, we cotreated human colorectal cancer cells (Caco-2) with the small-molecule inhibitors and hydrogen peroxide or the approved drug temozolomide. Interestingly, the tested compounds sensitized Caco-2 cells to both genotoxic agents in a DNA repair pathway-dependent manner.
authors.affiliation: Departments of Chemistry and Biology, Konstanz Research School Chemical Biology, University of Konstanz , Universitätsstrasse 10, 78457 Konstanz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Strittmatter
authors.forename: Anette
authors.initials: A
authors.lastname: Brockmann
authors.forename: Moritz
authors.initials: M
authors.lastname: Pott
authors.forename: Annika
authors.initials: A
authors.lastname: Hantusch
authors.forename: Thomas
authors.initials: T
authors.lastname: Brunner
authors.forename: Andreas
authors.initials: A
authors.lastname: Marx
mesh_terms: D018938:Caco-2 Cells; D015179:Colorectal Neoplasms / Q000188:drug therapy; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D012236:Rhodanine / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D012236:Rhodanine; C415367:DNA polymerase beta2; D019951:DNA Polymerase beta