title: Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1.
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.
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Bachovchin
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Zuhl
authors.forename: Anna E
authors.initials: AE
authors.lastname: Speers
authors.forename: Monique R
authors.initials: MR
authors.lastname: Wolfe
authors.forename: Eranthie
authors.initials: E
authors.lastname: Weerapana
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Brown
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D020543:Proteome / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C561637:2-(4-fluorophenylsulfonyl)-3-(1-(3-nitrophenylsulfonyl)-1H-pyrrol-2-yl)acrylonitrile; D020543:Proteome; D013449:Sulfonamides; D013450:Sulfones; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1; D000181:Acrylonitrile