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Remsberg, Jarrett R; Suciu, Radu M; Zambetti, Noemi A; Hanigan, Thomas W; Firestone, Ari J; Inguva, Anagha; Long, Amanda; Ngo, Nhi; Lum, Kenneth M; Henry, Cassandra L; Richardson, Stewart K; Predovic, Marina; Huang, Ben; Dix, Melissa M; Howell, Amy R; Niphakis, Micah J; Shannon, Kevin; Cravatt, Benjamin F
Nature chemical biology, 08/2021, Volume: 17, Issue: 8Journal Article
Multiple Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M (Palm M) block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared with Palm M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MAP kinase kinase (MEK) inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes as regulators of the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.
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