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X-ray structures of checkpoint kinase 2 in complex with inhibitors that target its gatekeeper-dependent hydrophobic pocket

  1. Author:
    Lountos, G. T.
    Jobson, A. G.
    Tropea, J. E.
    Self, C. R.
    Zhang, G. T.
    Pommier, Y.
    Shoemaker, R. H.
    Waugh, D. S.

  2. Author Address

    [Lountos, GT; Tropea, JE; Waugh, DS] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Lountos, GT] SAIC Frederick, Basic Sci Program, Frederick, MD 21702 USA. [Jobson, AG; Pommier, Y] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Self, CR; Zhang, GT] Provid Pharmaceut, Monmouth Jct, NJ 08852 USA. [Shoemaker, RH] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA.;Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA;waughd@mail.nih.gov
    1. Year: 2011
    2. Date: Oct
  2. Journal: Febs Letters
    1. 585
    2. 20
    3. Pages: 3245-3249
  4. Type of Article: Article
  5. ISSN: 0014-5793
  1. Abstract:

    The serine/threonine checkpoint kinase 2 (Chk2) is an attractive molecular target for the development of small molecule inhibitors to treat cancer. Here, we report the rational design of Chk2 inhibitors that target the gatekeeper-dependent hydrophobic pocket located behind the adenine-binding region of the ATP-binding site. These compounds exhibit IC(50) values in the low nanomolar range and are highly selective for Chk2 over Chk1. X-ray crystallography was used to determine the structures of the inhibitors in complex with the catalytic kinase domain of Chk2 to verify their modes of binding. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

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External Sources

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  2. DOI: 10.1016/j.febslet.2011.08.050
  3. View record in Web of Science®
  4. WOS: 000296514100015

Library Notes

  1. Fiscal Year: FY2011-2012
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