S-palmitoylation is a post-translational modification in which palmitate is attached to the cysteine residue of a protein through a thioester linkage. An estimated 10% of human proteins are palmitoylated and this modification is known to play a functional role in the activity of several disease-relevant targets. Despite great interest in palmitoylation, methods for modulating protein palmitoylation in cells are limited. Because of this, we aimed to develop a small molecule capable of direct and chemoselective cleavage of S-palmitoyl groups in vivo. Towards this end, we designed an amphiphilic molecule with a thioester-reactive cysteine headgroup and a lipophilic tail. We hypothesized that this design would balance lipophilicity and aqueous solubility and promote both cell permeability and affinity for cellular membranes. Using this approach, we can efficiently cleave S-palmitoyl groups from a range of endogenous proteins including the native GTPase HRas. Depalmitoylation of HRas in an HRas mutant bladder cancer cell line inhibits downstream cancer signaling and demonstrates that this technique may have potential therapeutic applications.

Small molecules for functional protein depalmitoylation

2019 Fall National Meeting

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