Design of Bivalent SMAC Mimetics

二价 SMAC 模拟物的设计

• 批准号: 8007411
• 负责人: SHAOMENG WANG
• 金额: $ 30.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8007411
• 关键词: Affinity; Americas; Animal Model; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Inhibitor; Apoptosis Regulator; Apoptotic; Applications Grants; BIR Domain; Benchmarking; Binding; Biological Assay; Cancer Patient; Cancer cell line; Cause of Death; Cell-Free System; Cells; Complex; Data; Development; Drug Design; Drug Kinetics; Family member; Foundations; Gel Chromatography; Goals; Grant; Health; Human; In Vitro; Induction of Apoptosis; Inhibitory Concentration 50; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Modeling; Modification; Molecular Mechanisms of Action; Molecular Target; Mus; Normal Cell; Outcome; Peptides; Performance; Protein Family; Proteins; Research; Research Design; Research Project Grants; Resistance; Resolution; Solid; Specificity; Structure-Activity Relationship; Therapeutic; Time; Toxic effect; Tumor Tissue; United States; X-linked IAP; Xenograft Model; base; cancer cell; cancer therapy; caspase-3; caspase-7; caspase-9; cell growth; design; effective therapy; human BIRC4 protein; improved; in vivo; inhibitor-of-apoptosis protein; inhibitor/antagonist; insight; malignant breast neoplasm; mimetics; novel; overexpression; pre-clinical; protein function; small molecule; success; three dimensional structure; tumor

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.

描述（由申请人提供）：凋亡蛋白（IAP）的抑制剂是一类中心凋亡调节剂和有效的内源性凋亡抑制剂。 IAP蛋白代表了旨在克服癌细胞凋亡耐药性的抗癌药物设计的新的且高度有希望的分子靶标。 SMAC/Diablo是一种最近鉴定出的蛋白质，直接与IAP蛋白质相互作用，并作为IAP的直接内源性拮抗剂起作用，是细胞中有效的促凋亡分子。基于SMAC蛋白的高分辨率三维结构和与X连接IAP（XIAP）复合物中的肽，我们最近设计并合成了一类有效的，非肽，可渗透，可渗透，小分子SMAC SMAC MIMIMETIC，靶向两个域的域。我们的初步数据清楚地表明，我们有希望的铅化合物可能具有巨大的治疗人类癌症的治疗潜力。我们的长期目标是将高度有效的小分子SMAC模拟物作为一种全新的抗癌疗法，用于治疗人类癌症。为了实现我们的长期目标，我们将在这笔赠款中执行以下三个特定目标。具体目的1：进行体内研究以确定人类癌症动物模型中最有希望的SMAC模拟物的毒性，药代动力学和抗肿瘤活性以及作用机理。特定目标2：根据有希望的铅化合物设计，合成新颖和有效的非肽SMAC模拟物；特定目标3。（a）。确定它们与IAP蛋白的结合亲和力； （b）确定它们在功能测定中拮抗IAP蛋白功能的能力； （c）。研究其与IAP蛋白的结合模型。特定目标4：（a）。确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）。进行体外研究以获取对分子作用机理的详细见解。成功进行的研究将通过克服癌细胞对细胞凋亡的抗药性，从而导致一类全新的分子抗癌疗法的全新分子抗癌疗法的发展。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结果。该研究项目旨在设计，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。