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Structure-Based Design, Synthesis, Evaluation, and Crystallographic Studies of Conformationally Constrained Smac Mimetics as Inhibitors of the X-linked Inhibitor of Apoptosis Protein (XIAP)
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    Structure-Based Design, Synthesis, Evaluation, and Crystallographic Studies of Conformationally Constrained Smac Mimetics as Inhibitors of the X-linked Inhibitor of Apoptosis Protein (XIAP)
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    Departments of Internal Medicine, Biological Chemistry, Pharmacology, Medicinal Chemistry, Radiation Oncology, Comprehensive Cancer Center, Life Sciences Institute, Biophysics Research Division, University of Michigan, Ann Arbor, Michigan 48109
    †Coordinates of compound 21 in complex with XIAP BIR3 and structural factors have been deposited in the RCSB Protein Data Bank (access code 2JK7).
    * To whom correspondence should be addressed. Phone: 734-615-0362. Fax: 734-647-9647. E-mail: [email protected]
    ‡Department of Internal Medicine, University of Michigan.
    §Department of Biological Chemistry, University of Michigan.
    ∥Department of Pharmacology, University of Michigan.
    ⊥Department of Medicinal Chemistry, University of Michigan.
    #Department of Radiation Oncology, University of Michigan.
    ∇Comprehensive Cancer Center, University of Michigan.
    ○Life Sciences Institute, University of Michigan.
    ▲Biophysics Research Division, University of Michigan.
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2008, 51, 22, 7169–7180
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    https://doi.org/10.1021/jm8006849
    Published October 28, 2008
    Copyright © 2008 American Chemical Society

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    Small molecules designed to mimic the binding of Smac protein to X-linked inhibitor of apoptosis protein (XIAP) are being pursued as a promising new class of anticancer drugs. Herein, we report the design, synthesis, and comprehensive structure−activity relationship studies of a series of conformationally constrained bicyclic Smac mimetics. Our studies led to the discovery of a number of highly potent and cell-permeable Smac mimetics and yielded important new insights into their structure−activity relationship for their binding to XIAP and for their activity in inhibition of cancer cell growth. Determination of the crystal structure of one potent Smac mimetic, compound 21, in complex with XIAP BIR3 provides the structural basis for its high-affinity binding to XIAP and for the design of highly potent Smac mimetics.

    Copyright © 2008 American Chemical Society

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    Elemental analysis data for compounds 1627. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2008, 51, 22, 7169–7180
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm8006849
    Published October 28, 2008
    Copyright © 2008 American Chemical Society

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    Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

    Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

    The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.