Design of Bivalent SMAC Mimetics

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Abstract: The inhibitors of apoptosis proteins (IAPs) are a class of central apoptosis regulators and potent endogenous apoptosis inhibitors. IAP proteins represent new and highly promising molecular targets for anti-cancer drug design aiming at overcoming apoptosis resistance of cancer cells. Smac/DIABLO, a recently identified protein, directly interacts with IAP proteins and functions as a direct endogenous antagonist of IAPs and is a potent pro-apoptotic molecule in cells. Based on high-resolution three-dimensional structures of Smac protein and peptide in complex with X-linked IAP (XIAP), we have recently designed and synthesized a class of potent, non-peptide, cell-permeable, small- molecule Smac mimetics that target two domains of XIAP. Our preliminary data clearly demonstrate that our promising lead compound may have great therapeutic potential for the treatment of human cancer. Our long-term goal is to develop highly potent, small- molecule Smac mimetics as an entirely new type of anti-cancer therapy for the treatment of human cancer. Toward our long-term goal, we will perform the following three Specific Aims in this grant. Specific Aim 1: To perform in vivo studies to determine the toxicity, pharmacokinetics and anti-tumor activity and mechanism of action of the most promising Smac mimetics in animal models of human cancer. Specific Aim 2: To design, synthesize novel and potent non-peptide Smac mimetics based upon the promising lead compound; Specific Aim 3. (a). To determine their binding affinities to IAP proteins; (b) To determine their ability to antagonize the function of IAP proteins in functional assays; (c). To investigate their binding models to IAP proteins. Specific Aim 4: (a). To determine their activity in human cancer cells and their selectivity over normal cells. (b). To perform in vitro studies to gain detailed insights into the molecular mechanism of action. Successfully carried out, our proposed research will lead to the development of an entirely new class of molecularly targeted anticancer therapy for the treatment of human cancer by overcoming resistance of cancer cells to apoptosis.