Thursday, May 21, 2020

ABHD17 enzymes regulate dynamic plasma membrane palmitoylation and N-Ras-dependent cancer growth [@MJNiphakis]

Jarrett R Remsberg, Radu M Suciu, Noemi A Zambetti, Thomas W Hanigan, Ari J Firestone, Anagha Inguva, Amy Long, Nhi Ngo, Kenneth M Lum, Cassandra L Henry, Stewart K Richardson, Marina Predovic, Ben Huang, Amy R Howell, Micah J Niphakis, Kevin Shannon, Benjamin F Cravatt
bioRxiv, 2020
 doi: https://doi.org/10.1101/2020.05.21.108316

A subset of 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 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 to Palmostatin 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 MEK inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes in modulating the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers

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Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1

Adrian Hall, Jan Abendroth, Madison J. Bolejack, Tom Ceska, Sylvie Dell’Aiera, Victoria Ellis, David Fox, Cyril François, Muigai M. Muruthi,...