Abstract
Epidemiological evidence, preclinical studies and prospective phase II studies in humans indicate that the isoflavone, genistein, will inhibit the conversion of human prostate cells to an invasive, and ultimately, a metastatic phenotype. Though promising, genistein exerts many additional effects that have the potential for future toxicity in humans. We therefore sought to discover a new drug with improved efficacy and most importantly, with high specificity. Starting from an isoflavone chemical scaffold, we employed a fragment-based chemical synthesis diversification approach, and coupled it to three in vitro screens: 1) cell invasion (efficacy), 2) cell growth inhibition (an indicator of general toxicity), and 3) several measures of estrogenic activity. From multiple synthesis/biological assay iterations we developed a refined structure-activity relationship map, thereby leading us to discover KBU2046. KBU2046 represents a new and chemically distinct class of bioactive compounds. It has greater anti-invasion efficacy than genistein, and more importantly, no cell toxicity or estrogenic activity. Extensive toxicity studies in mice were negative. At low nanomolar blood concentrations, KBU2046 will prevent orthotopically implanted human prostate cancer cells from forming metastasis in a dose-responsive fashion. In summary, we have successfully discovered and developed a compound that prevents progression to a metastatic phenotype for human prostate cancer. We are in the process of bringing KBU2046 into the clinic, with the goal of preventing death from the second most common cause of cancer related death in men.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):B58.
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