The goal of this Phase I proposal is to develop a novel small molecule anti-cancer therapeutic to treat malignant melanoma. The strategy will be to screen for inhibitors of a mutant form of the protein kinase B-Raf. It has recently been reported that the V599E mutation in B-Raf is present in over half of all human malignant melanomas, and causes constitutive activation of the MAP kinase signal transduction pathway, promoting continuous cell proliferation. If detected early, malignant melanoma, as a cancer of the skin, has a high cure rate when surgically excised before it metastasizes. Metastatic melanoma, in contrast, is a highly aggressive and later stage disease that is virtually incurable. While the incidence of all cancers in the U.S. has shown a net decrease of 7.1% over the last six years, the incidence of melanoma has increased by 24.8% during that same time period, demonstrating a growing need for an effective therapy. An anti-cancer drug which targets mutant B-Raf protein kinase has the potential to cause a paradigm shift in the way malignant melanoma is currently treated, particularly metastatic disease. The goals for this proposal is to I) Discover at least five B-Raf kinase inhibitors or lead series from a high throughput screen; ii) Identify at least two compounds with biological activity that inhibit the MAP kinase signal transduction pathway in two human melanoma cell lines; and iii) Identify at least one cellular active that inhibits proliferative activity or reduces viability of a V599E B-Raf expressing melanoma cell line, and test for differential growth inhibition between normal human and B-Raf mutant tumor cell lines. ? ? ?
