A major goal of
personalized medicine in oncology is the identification of drugs with predictable efficacy based on a specific trait of the
cancer cell, as has been demonstrated with
gleevec (presence of Bcr-Abl
protein),
herceptin (Her2 overexpression), and
iressa (presence of a specific EGFR mutation). This is a challenging task, as it requires identifying a cellular component that is altered in
cancer, but not normal cells, and discovering a compound that specifically interacts with it. The
enzyme NQO1 is a potential target for
personalized medicine, as it is overexpressed in many solid
tumors. In normal cells NQO1 is inducibly expressed, and its major role is to detoxify
quinones via bioreduction; however, certain
quinones become more toxic after reduction by NQO1, and these compounds have potential as selective
anticancer agents. Several
quinones of this type have been reported, including
mitomycin C, RH1,
EO9,
streptonigrin, β-
lapachone, and
deoxynyboquinone (DNQ). However, no unified picture has emerged from these studies, and the key question regarding the relationship between NQO1 processing and anticancer activity remains unanswered. Here, we directly compare these
quinones as substrates for NQO1 in vitro, and for their ability to kill
cancer cells in culture in an NQO1-dependent manner. We show that DNQ is a superior NQO1 substrate, and we use computationally guided design to create DNQ analogues that have a spectrum of activities with NQO1. Assessment of these compounds definitively establishes a strong relationship between in vitro NQO1 processing and induction of
cancer cell death and suggests these compounds are outstanding candidates for selective anticancer
therapy.