Protein S-palmitoylation is a reversible post-translational modification that is present on proteins involved in numerous biophysical processes, such as cellular trafficking, lipid raft association, and protein complex formation. Specifically, S-palmitoylation plays a significant role in the signal transduction pathway of the oncogenic N-Ras protein, which is mutated in many cancers such as hematopoietic tumors. This post-translational modification allows N-Ras to traffick from the Golgi to the plasma membrane, thus enabling its downstream signaling cascade. Mutations in N-Ras lead to an overactive protein that turns on downstream proteins involved in the cell growth and survival pathways, which contribute to cancer. Many of the Ras inhibitors that focus on directly blocking the addition of the farnesyl lipid modification to the oncogenic N-Ras protein have failed in clinical trials because of enzymatic redundancy. In addition, the irreversible S-palmitoylation inhibitor 2-bromopalmitate (2-BP) is used as a pharmacological tool to study protein palmitoylation, but it is non-selective and inhibits many important enzymes in lipid metabolism. Therefore, directly targeting the palmitoylation modification of N-Ras can be an approach used to inhibit N-Ras oncogenic activity by preventing association with the plasma membrane using compounds capable of cleaving endogenous S-palmitoyl modifications. Our group has synthesized a class of molecules capable of chemoselective reactions with long chain thioesters, which result in the efficient release of a free thiol. Selective and reversible chemical agents for depalmitoylation would enable temporal control over N-Ras lipidation and allow for the study of its palmitoylation and trafficking kinetics <i>in vivo</i>. By using methods, such as live-cell imaging and western blotting, we can study N-Ras protein lipidation interactions as well as downstream signaling pathways affected by cleaving of the S-palmitoyl protein modification. Additionally, these compounds could serve as new drug candidates able to intercept and shut down cancer signaling through a novel mechanism.

Targeted depalmitoylation of N-Ras for suppression of oncogenic signaling pathways

255th National Meeting (2018)

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