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Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1

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Overview

related to degree

  • Zuhl, Andrea M., Ph.D. in Chemistry, Scripps Research 2006 - 2012
  • Bachovchin, Daniel A., Ph.D. in Chemistry, Scripps Research 2006 - 2011

authors

  • Bachovchin, Daniel A.
  • Zuhl, Andrea M.
  • Speers, Anna
  • Wolfe, M. R.
  • Weerapana, E.
  • Brown, S. J.
  • Rosen, Hugh
  • Cravatt, Benjamin

publication date

  • July 2011

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • The serine hydrolase protein phosphatase methylesterase-1 (PME-1) regulates the methylesterification state of protein phosphatase 2A (PP2A) and has been implicated in cancer and Alzheimer's disease. We recently reported a fluorescence polarization-activity-based protein profiling (fluopol-ABPP) high-throughput screen for PME-1 that uncovered a remarkably potent and selective class of aza-β-lactam (ABL) PME-1 inhibitors. Here, we describe a distinct set of sulfonyl acrylonitrile inhibitors that also emerged from this screen. The optimized compound, 28 (AMZ30), selectively inactivates PME-1 and reduces the demethylated form of PP2A in living cells. Considering that 28 is structurally unrelated to ABL inhibitors of PME-1, these agents, together, provide a valuable set of pharmacological probes to study the role of methylation in regulating PP2A function. We furthermore observed that several serine hydrolases were sensitive to analogues of 28, suggesting that more extensive structural exploration of the sulfonyl acrylonitrile chemotype may result in useful inhibitors for other members of this large enzyme class.

subject areas

  • Acrylonitrile
  • Carboxylic Ester Hydrolases
  • Cell Line
  • Humans
  • Proteome
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides
  • Sulfones
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Identity

PubMed Central ID

  • PMC3144155

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm200502u

PubMed ID

  • 21639134
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Additional Document Info

start page

  • 5229

end page

  • 5236

volume

  • 54

issue

  • 14

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