Design of Bivalent SMAC Mimetics

描述（由申请人提供）：凋亡蛋白抑制剂（IAPs）是一类中心细胞凋亡调节剂和有效的内源性细胞凋亡抑制剂。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抗性。Smac/DIABLO是最近发现的一种蛋白，可直接与IAP蛋白相互作用，并作为IAP的直接内源性拮抗剂，是细胞中一种有效的促凋亡分子。基于X-linked IAP复合物（XIAP）中Smac蛋白和肽的高分辨率三维结构，我们最近设计并合成了一类针对XIAP的两个结构域的有效的、非肽的、细胞渗透性的小分子Smac模拟物。我们的初步数据清楚地表明，我们的先导化合物在治疗人类癌症方面可能具有很大的治疗潜力。我们的长期目标是开发高效的小分子Smac模拟物，作为一种全新的抗癌疗法，用于治疗人类癌症。为了达到我们的长期目标，我们将在此奖助金中执行以下三个具体目标。具体目标1：在人类癌症动物模型中进行体内研究，以确定最有前途的Smac模拟物的毒性、药代动力学、抗肿瘤活性和作用机制。具体目标2：基于有前途的先导化合物设计、合成新的有效的非肽Smac模拟物；具体目标3。(一)。测定其与IAP蛋白的结合亲和力；(b)在功能分析中确定其拮抗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)。测定它们在人类癌细胞中的活性及其对正常细胞的选择性。(b)。进行体外研究，以深入了解作用的分子机制。如果成功进行，我们提出的研究将导致一种全新的分子靶向抗癌疗法的发展，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：癌症是美国第二大死亡原因。迫切需要更有效的治疗方法来改善数百万癌症患者的预后。本研究项目旨在设计、合成和开发一类新的小分子抗癌药物，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.