Design of Bivalent SMAC Mimetics

说明书(申请人提供)：凋亡抑制蛋白(IAPs)是一类中枢细胞凋亡调节因子和有效的内源性细胞凋亡抑制因子。IAP蛋白为抗癌药物设计提供了新的、极具前景的分子靶点，旨在克服癌细胞的凋亡抵抗。Smac/Diablo是新近发现的一种蛋白，它直接与IAP蛋白相互作用，是IAP的内源性直接拮抗剂，是细胞内一种强有力的促凋亡分子。基于Smac蛋白和多肽在XIAP复合体(XIAP)中的高分辨率三维结构，我们最近设计并合成了一类针对XIAP两个结构域的有效的、非肽的、细胞通透性的小分子Smac模拟物。我们的初步数据清楚地表明，我们前景看好的先导化合物可能在治疗人类癌症方面具有巨大的治疗潜力。我们的长期目标是开发高效、小分子的Smac模拟物，作为治疗人类癌症的一种全新的抗癌疗法。为了实现我们的长期目标，我们将在这笔赠款中实现以下三个具体目标。具体目标1：进行体内研究，以确定最有希望的Smac类似物在人类癌症动物模型中的毒性、药代动力学和抗肿瘤活性及其作用机制。具体目标2：以前景看好的先导化合物为基础设计、合成新型有效的非肽Smac模拟物；具体目标3。确定它们与IAP蛋白的结合亲和力；(B)在功能分析中确定它们对抗IAP蛋白功能的能力；(C)研究它们与IAP蛋白的结合模式。具体目标4：(A)。以确定它们在人类癌细胞中的活性以及它们对正常细胞的选择性。(B)。进行体外研究，以获得对分子作用机制的详细了解。如果成功开展，我们提议的研究将导致开发一种全新的分子靶向抗癌疗法，通过克服癌细胞对凋亡的抵抗来治疗人类癌症。公共卫生相关性：癌症是美利坚合众国第二大死因。迫切需要更有效的治疗来改善数百万癌症患者的预后。本研究项目旨在设计、合成和开发一类新型小分子抗癌药物，用于治疗人类癌症，包括但不限于乳腺癌和前列腺癌。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE:Cancer is the second leading cause of death in the United State of America. More effective treatments are urgently needed to improve the outcome of millions of cancer patients. This research project aims at the design, synthesis and development of a new class of small-molecule anti- cancer drugs for the treatment of human cancer, including but not limited to breast cancer and prostate cancer.