Development of Anti-Prenylated Protein Therapies for Lung Cancer

Lung cancer is the number one cause of cancer-related death for both men and women in the United States and will kill approximately 4,450 Kentucky citizens this year. Substantial evidence points to the central role of proteins normally modified by a prenyl group in lung cancer progression. Mutated forms of the prenylated protein K-Ras are found in 20-30% of all non-small cell lung cancer (NSCLC). There are two types of prenyl groups, the farnesyl group attached to proteins by the enzyme FTase and the geranylgeranyl group attached by the related enzyme GGTase 1. Prenylation is essential for proper function ofthe modified proteins and K-Ras is normally farnesylated. Farnesylation of Ras and other proteins is inhibited by a new class of anti-cancer dmgs called farnesyltransferase inhibitors (FTI) which reduce the growth of lung tumor cells in cell culture and animal models. However, FTIs have shown little efficacy as single agents in human lung cancer clinical trials. Proteins clitical for cell survival, including K-Ras, evade the action ofFTIs by becoming geranylgeranylated by GGTase 1. Geranylgeranylated K-Ras is fully functional and GGTase I is not inhibited by FTls. We propose to develop a novel class of K-Ras function inhibitors that would bypass the evasion of the FTIs and lead to new treatments for lung cancer. We seek to modify K-Ras in an FTase dependent fashion with unnatural prenyl groups that prevent K-Ras function. We have prepared and tested a variety of unique, dmg-like molecules that hold great promise as lung cancer therapies.