ABSTRACT
BACKGROUND: The KRAS oncogene has a high prevalence in solid malignancies. Targeting KRAS and inappropriate activation of the MAPK pathway with novel drugs is of interest. This study developed and screened a library of compounds designed to inhibit KRAS signaling by altering prenyl function. MATERIALS AND METHODS: To screen a library of novel farnesyl analogs for their anticancer activity in human lung cancer and breast cancer cell lines. To evaluate if the designed and actual pharmacology are congruent. RESULTS: Sixty-seven novel compounds were tested and 70% of them screened positive for activity in at least one cell line. Two active compounds inhibited phosphorylation of MAP kinase consistent with KRAS inhibition. CONCLUSION: Although 47 of the 67 novel agents screened positive for activity, none of them were highly potent. However, targeting RAS with compounds that compete with farnesyl and geranylgeranyl modification of the protein remains viable and further work is already underway to create second generation molecules.
