270262-95-8Relevant articles and documents
Expanding the scope of human DNA polymerase and inhibitors
Strittmatter, Tobias,Brockmann, Anette,Pott, Moritz,Hantusch, Annika,Brunner, Thomas,Marx, Andreas
, p. 282 - 290 (2014/06/09)
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 γand β(pol γandβ ) 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 polβ . Importantly, 10 of these small-molecules selectively inhibited polβ and not the homologous polβ . We discovered 14 small-molecules that target polγ and found out that they are more potent than known inhibitors. We also investigated whether the discovered compounds sensitize cancer cells toward DNAdamaging 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.2013 American Chemical Society.
