Inhibition of NRAS Signaling in Melanoma through Direct Depalmitoylation Using Amphiphilic Nucleophiles.

ABSTRACT: Activating mutations in the small GTPase NRAS are responsible for driving tumor growth in several cancers. Unfortunately, the development of NRAS inhibitors has proven difficult due to the lack of hydrophobic binding pockets on the protein's surface. To overcome this limitation, we chose to target the post-translational S-palmitoyl modification of NRAS, which is required for its signaling activity. Utilizing an amphiphile-mediated depalmitoylation (AMD) strategy, we demonstrate the ability to directly cleave S-palmitoyl groups from NRAS and inhibit its function. C8 alkyl cysteine causes a dose-dependent decrease in NRAS palmitoylation and inhibits downstream signaling in melanoma cells with an activating mutation in NRAS. This compound reduces cell growth in NRAS-driven versus non-NRAS-dri

SUBMITTER: Vora HD 

PROVIDER: S-EPMC7556697 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature