title: Development of antiproliferative phenylmaleimides that activate the unfolded protein response.
abstract: The current paper presents the synthesis and evaluation of a series of maleimides that were designed to inhibit the Cdc25 phosphatase by alkylation of catalytically essential cysteine residues. Although in HepB3 cell culture assays the analogues did exhibit antiproliferative IC(50) values ranging from sub-micromolar to greater than 100 microM, inhibition of Cdc25 through cysteine alkylation could not be demonstrated. It was also found that analysis using fluorescence activated cell sorting (FACS) following treatment with the most potent analogue (1t) did not provide data consistent with inhibition at one specific point in the cell cycle, as would be expected if Cdc25A were inhibited. Further studies with a subset of analogues resulted in a correlation of antiproliferative potencies with activation of the unfolded protein response (UPR). The UPR is a regulatory pathway that temporarily suspends protein production when misfolding of proteins occurs within the endoplastic reticulum (ER). In addition, ER chaperones that promote proper refolding become up-regulated. If cellular damage cannot be resolved by these mechanisms, then the UPR can initiate apoptosis. The current study indicates that these maleimide analogues lead to UPR activation, which is predictive of the selective antiproliferative activity of the series.
authors.affiliation: Chemical Biology Laboratory, Molecular Discovery Program, NCI-Frederick, Frederick, MD 21702, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Muus
authors.forename: Curtis
authors.initials: C
authors.lastname: Hose
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.forename: Teresa
authors.initials: T
authors.lastname: Kosakowska-Cholody
authors.forename: David
authors.initials: D
authors.lastname: Farnsworth
authors.forename: Marzena
authors.initials: M
authors.lastname: Dyba
authors.forename: George T
authors.initials: GT
authors.lastname: Lountos
authors.forename: David S
authors.initials: DS
authors.lastname: Waugh
authors.forename: Anne
authors.initials: A
authors.lastname: Monks
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Michejda
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D056811:Unfolded Protein Response; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008301:Maleimides; D020687:cdc25 Phosphatases
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