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Small-Molecule Inhibitors of Protein-Protein Interactions pp 89–113Cite as

Design of Small-Molecule Smac Mimetics as IAP Antagonists

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 348))

Abstract

Smac/DIABLO, discovered in 2000 as a protein released from mitochondria into the cytosol in response to apoptotic stimuli, functions as an endogenous antagonist of X-linked inhibitor of apoptosis protein (XIAP) and several other IAP proteins through direct binding. The interaction between Smac and IAPs involves the AVPI tetrapeptide binding motif on the N-terminus of Smac and a well-defined groove on the surface of these IAP proteins, providing an ideal site for the design of small-molecule Smac mimetics. Potent and cell-permeable small-molecule Smac mimetics have provided powerful pharmacological tools for study of the regulation of apoptosis by IAP proteins, and several such compounds are now in early clinical trials as new anticancer agents.

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Acknowledgments

We are grateful for the financial support from the Breast Cancer Research Foundation, the Prostate Cancer Foundation, the Department of Defense Prostate Cancer Program (W81XWH-04-1-0213), Ascenta Therapeutics, and the National Cancer Institute, NIH (5R01CA109025 and 5R01CA127551). We thank Dr. G.W.A. Milne for his critical reading of the manuscript and Ms. Karen Kreutzer for her excellent secretarial assistance. The author thanks the present and past members of the Wang laboratory and all the collaborators, who have contributed to the design and evaluations of small-molecule Smac mimetics. The author is grateful for colleagues at Ascenta Therapeutics Inc. for advancing SM-406 (AT-406) into clinical development.

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Authors and Affiliations

  1. Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA

    Shaomeng Wang

  2. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Shaomeng Wang

  3. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA

    Shaomeng Wang

  4. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA

    Shaomeng Wang

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  1. Shaomeng Wang
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Correspondence to Shaomeng Wang .

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Editors and Affiliations

  1. Roche Research Center, Dept. Discovery Oncology, Hoffmann-La Roche Inc., Kingsland Street 340, Nutley, 07110-1199, New Jersey, USA

    Lyubomir Vassilev

  2. Roche Research Center, Dept. of Discovery Oncology, Hoffmann-La Roche Inc., Kingsland Street 340, Nutley, 07110, New Jersey, USA

    David Fry

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Wang, S. (2010). Design of Small-Molecule Smac Mimetics as IAP Antagonists. In: Vassilev, L., Fry, D. (eds) Small-Molecule Inhibitors of Protein-Protein Interactions. Current Topics in Microbiology and Immunology, vol 348. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_111

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