2. Academic Validation
  3. ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth

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

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. MIIP@lundbeck.com.
  • 7 Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. Kevin.Shannon@ucsf.edu.
  • 8 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Kevin.Shannon@ucsf.edu.
  • 9 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. cravatt@scripps.edu.
  • # 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-142161
    99.46%, ABHD17抑制剂
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