Pyrazole and pyrimidine phenylacylsulfonamides as dual Bcl-2/Bcl-xL antagonists

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Abstract

5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines.

References and notes (17)

  • J.E. Chipuk et al.

    Trends Cell Bio.

    (2008)
    R.J. Youle et al.

    Nature Rev. Mol. Cell Biol.

    (2008)
    B. Leber et al.

    Oncogene

    (2010)
    S.W.G. Tait et al.

    Nature Rev. Mol. Cell Bio.

    (2010)
  • S. Barelier et al.

    J. Med. Chem.

    (2010)
  • O. Sperandio et al.

    Drug Discov. Today

    (2010)
  • C.G. Cummings et al.

    Curr. Opin. Chem. Biol.

    (2010)
  • M. Vogler et al.

    Cell Death Differ.

    (2009)
  • M. Bruncko et al.

    J. Med. Chem.

    (2007)
    C.-M. Park et al.

    J. Med. Chem.

    (2008)
  • C. Tse et al.

    Cancer Res.

    (2008)
    S. Ackler et al.

    Cancer Chemother. Phamacol.

    (2010)
  • M. Vogler et al.

    Clin. Cancer Res.

    (2010)
There are more references available in the full text version of this article.

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Authors contributed equally to the composition of this manuscript.

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Current address: Hoffman-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.

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