Design, Synthesis and Evaluation of New Inhibitors of DNA G4 Unfolding by DHX36 helicase

The quadruplex DNA structures formed by the guanine-rich sequences (G4) present in promoter regions of oncogenes, like c-MYC, are emerging as selective anticancer drug targets, with two molecules in phase I clinical trials. G4s are dynamic structures regulating several genome processes and being regulated by helicases. Moreover, not only oncogene promoter G4s are increased in cancer cells, but also helicases are overexpressed in these cells, thus making these two genome regulators attractive targets for anticancer intervention. Herein we disclose the structure of a new small molecule with high affinity and selectivity to the cMYCG4 (Kb = 6.7 ± 0.6 x 10^6 M^-1 or KD= 0.15 ± 0.01 µM), capacity to inhibit the activity of the helicase DHX36 with Ki ~ 7 µM and antiproliferative activity in breast cancer cells overexpressing c-MYC, with IC50 values also in the low µM range. Importantly, due to the reduced number of protonable groups, this new inhibitor of DHX36-mediated G4-unfolding activity is a better drug lead molecule than the previously reported ones. The mechanism of action of this compound in breast cancer cells is now being investigated.