Small molecules that deter the functions of DNA damage response machinery are postulated to be useful for enhancing the
DNA damaging effects of
chemotherapy or ionizing radiation treatments to combat
cancer by impairing the proliferative capacity of rapidly dividing cells that accumulate replicative lesions. Chemically induced or genetic synthetic lethality is a promising area in
personalized medicine, but it remains to be optimized. A new target in
cancer therapy is
DNA unwinding
enzymes known as helicases. Helicases play critical roles in all aspects of
nucleic acid metabolism. We and others have investigated small molecule targeted inhibition of helicase function by compound screens using biochemical and cell-based approaches. Small molecule-induced trapping of
DNA helicases may represent a generalized mechanism exemplified by certain topoisomerase and
PARP inhibitors that exert poisonous consequences, especially in rapidly dividing
cancer cells. Taking the lead from the broader field of DNA repair inhibitors and new information gleaned from structural and biochemical studies of
DNA helicases, we predict that an emerging strategy to identify useful helicase-interacting compounds will be structure-based molecular docking interfaced with a computational approach. Potency, specificity, drug resistance, and bioavailability of helicase inhibitor drugs and targeting such compounds to subcellular compartments where the respective helicases operate must be addressed. Beyond
cancer therapy, continued and new developments in this area may lead to the discovery of helicase-interacting compounds that chemically rescue clinically relevant helicase missense
mutant proteins or activate the catalytic function of wild-type
DNA helicases, which may have novel therapeutic application.