Inhibition of hAPE1 Activity by AP Site Specific Cisplatin Analogue

Abstract

Cisplatin is a representative first-generation anticancer drug still in use. But, strong cytotoxicity can cause various side effects, and even diverse analogues have been developed to compensate it, did not completely reduce this disadvantage. Even though strong cytotoxicity, the need for this anticancer drug is expected to increase steadily, and more improved analogues need to be discovered. We intend to propose an analogue which can be more toxic to cancer cells by targeting AP site which exist in a higher proportion in cancer cells than normal cells. If so, it will be possible to reduce the amount of drug required, which will help to reduce toxicity. In order to specifically target the AP site, cisplatin was modified according to two proposed purposes. (1) Base Stacking Model; induce base stacking around the AP site, (2) Complementary Base Modal; increased accessibility through base-pairing with a base across the AP site. To examine that these analogues really bind specifically to the AP site, the activity of hAPE1, which inhibited by the specific binding of the analogue to the AP site, was used. As a result, we have created a new cisplatin analogue with an ability of specific binding to the AP sites covalently. As it is an experiment at the in vitro level, it cannot be applied clinically. But, a new cisplatin analog with this mechanism can be discovered, and AP site can be raised as a new target for many other drugs.