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Development of antiproliferative phenylmaleimides that activate the unfolded protein response

  1. Author:
    Muus, U.
    Hose, C.
    Yao, W.
    Kosakowska-Cholody, T.
    Farnsworth, D.
    Dyba, M.
    Lountos, G. T.
    Waugh, D. S.
    Monks, A.
    Burke, T. R.
    Michejda, C. J.

  2. Author Address

    [Muus, Ulrike; Farnsworth, David; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Mol Discovery Program, Frederick, MD 21702 USA. [Hose, Curtis; Monks, Anne] SAIC Frederick Inc, Screening Technol Branch, Frederick, MD 21702 USA. [Yao, Wei; Michejda, Christopher J.] NCI, Struct Biophys Lab, Mol Discovery Program, Frederick, MD 21702 USA. [Kosakowska-Cholody, Teresa] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. [Dyba, Marzena] NCI, Struct Biophys Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Lountos, George T.; Waugh, David S.] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA.;Burke, TR, NCI, Biol Chem Lab, Mol Discovery Program, Frederick, MD 21702 USA.;tburke@helix.nih.gov
    1. Year: 2010
    2. Date: Jun
  2. Journal: Bioorganic & Medicinal Chemistry
    1. 18
    2. 12
    3. Pages: 4535-4541
  4. Type of Article: Article
  5. ISSN: 0968-0896
  1. 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 IC50 values ranging from sub-micromolar to greater than 100 mu M, 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. Published by Elsevier Ltd.

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External Sources

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  2. DOI: 10.1016/j.bmc.2010.04.057
  3. View record in Web of Science®
  4. WOS: 000278480900040

Library Notes

  1. Fiscal Year: FY2009-2010
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