ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth

  • Nat Chem Biol. 2021 Aug;17(8):856-864. doi: 10.1038/s41589-021-00785-8.
Jarrett R Remsberg   #  1 ,  Radu M Suciu   #  1 ,  Noemi A Zambetti   #  2  3 ,  Thomas W Hanigan  1 ,  Ari J Firestone  2  3 ,  Anagha Inguva  2 ,  Amanda Long  2 ,  Nhi Ngo  4 ,  Kenneth M Lum  4 ,  Cassandra L Henry  4 ,  Stewart K Richardson  5 ,  Marina Predovic  2 ,  Ben Huang  2  3 ,  Melissa M Dix  1 ,  Amy R Howell  5 ,  Micah J Niphakis  6 ,  Kevin Shannon  7  8 ,  Benjamin F Cravatt  9
Affiliations
  • 1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • 2. Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
  • 3. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • 4. Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA.
  • 5. Department of Chemistry, University of Connecticut, Storrs, CT, USA.
  • 6. Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA. [email protected].
  • 7. Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. [email protected].
  • 8. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. [email protected].
  • 9. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. [email protected].
  • # Contributed equally.
PMID: 33927411 DOI: 10.1038/s41589-021-00785-8
Abstract

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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-142161
    ABD957
    98.14%, ABHD17 Inhibitor
    target: MAGL
    Research Areas: Cancer