Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase II? Catalytic Inhibitors.

ABSTRACT: A study of structure-based modulation of known ligands of hTopoII?, an important enzyme involved in DNA processes, coupled with synthesis and in vitro assays led to the establishment of a strategy of rational switch in mode of inhibition of the enzyme's catalytic cycle. 6-Arylated derivatives of known imidazopyridine ligands were found to be selective inhibitors of hTopoII?, while not showing TopoI inhibition and DNA binding. Interestingly, while the parent imidazopyridines acted as ATP-competitive inhibitors, arylated derivatives inhibited DNA cleavage similar to merbarone, indicating a switch in mode of inhibition from ATP-hydrolysis to the DNA-cleavage stage of catalytic cycle of the enzyme. The 6-aryl-imidazopyridines were relatively more cytotoxic than etoposide in cancer cells and less toxic to normal cells. Such unprecedented strategy will encourage research on "choice-based change" in target-specific mode of action for rapid drug discovery.

SUBMITTER: Baviskar AT 

PROVIDER: S-EPMC4416441 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature