Post-translational modifications (PTMs) of proteins are involved in virtually all cellular signaling pathways.
Pharmacological intervention in these events is an important strategy for drug development. In this project, we
propose to establish a novel platform for the discovery of covalent inhibitors of cysteine post-translational
modifications, in particular, the prenylation of the C-termini of H-Ras and K-Ras. These events are critical for
oncogenic mutants of these proteins to drive cell uncontrolled growth and division. In contrast to typical
strategies for blocking PTMs, we will screen for non-peptidic macrocycles that bind covalently to the modified
epitope on the substrate protein (H-Ras or K-Ras), rather than compounds that target the modifying enzyme. In
this way, we believe it will be possible to manipulate single PTMs with unprecedented selectivity.