Design of Orally Bioavailable IAP Antagonists for Cancer Treatment

用于癌症治疗的口服生物可利用的 IAP 拮抗剂的设计

• 批准号: 8008750
• 负责人: SHAOMENG WANG
• 金额: $ 26.79万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8008750
• 关键词: Affinity; Americas; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulator; Binding; Bioavailable; Cancer Patient; Cancer cell line; Caspase; Cause of Death; Cessation of life; Data; Development; Dose; Drug Kinetics; Face; Foundations; Goals; Health; Human; In Vitro; Induction of Apoptosis; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mitochondria; Molecular Weight; Normal Cell; Oral; Outcome; Plasma; Play; Probability; Proteins; Regulation; Reporting; Research; Research Design; Research Project Grants; Resistance; Resources; Role; Solid; Specificity; Structure; Structure-Activity Relationship; Therapeutic Agents; Toxic effect; Tumor Tissue; United States; X-linked IAP; Xenograft Model; Xenograft procedure; analog; base; cIAP1 protein; cancer cell; cancer therapy; cell growth; design; drug development; effective therapy; human BIRC4 protein; improved; in vivo; inhibitor of apoptosis protein 2; inhibitor-of-apoptosis protein; malignant breast neoplasm; mimetics; neoplastic cell; novel; pre-clinical; pro-apoptotic protein; receptor; small molecule; success; therapeutic target; tumor; tumor growth

DESCRIPTION (provided by applicant): Inhibitor of apoptosis proteins (IAPs) are a class of key apoptosis regulators. Among these IAP proteins, cellular IAP-1 (cIAP-1) and cellular IAP-2 (cIAP-2) play critical roles in the regulation of death-receptor-mediated apoptosis, and X-linked IAP (XIAP) is a central regulator of both death-receptor-mediated and mitochondria-mediated apoptosis pathways. Because of their central role as apoptosis regulators, XIAP and cIAP-1/2 are promising cancer therapeutic targets. Smac is an endogenous antagonist of these IAP proteins and interacts with them via its AVPI tetrapeptide binding motif. In recent years, intense research efforts have been devoted to the design and development of small molecules known as Smac mimetics, which mimic the AVPI binding motif and function as antagonists of IAP proteins. Smac mimetics are not only capable of sensitizing cancer cells to induction of apoptosis by other therapeutic agents but also are effective as single agents in induction of apoptosis in vitro and in vivo in a subset of cancer cell lines of diverse tumor types. Smac mimetics are considered to have great potential for development as a new class of anticancer drugs. In this R01 competing renewal, we propose to evaluate a novel class of potent, orally active, promising Smac mimetics as new therapies for the treatment of human cancer. Our preliminary data have shown that our promising lead compounds bind to XIAP and cIAP-1/2 with affinities in the low nanomolar range, effectively induce apoptosis in cancer cells, possess minimal toxicity to normal cells and have a cellular mechanism of action highly consistent with targeting IAP proteins for apoptosis induction. One of our lead compounds is highly effective as an oral agent in induction of apoptosis in xenograft tumor tissues and in inhibition of tumor growth in the MDA- MB-231 xenograft model, while showing no toxicity to animals at highly efficacious doses. Our ultimate goal in this project is to develop a highly potent, orally active Smac mimetic as a new therapy for the treatment of human cancer. To maximize the probability of achieving our ultimate goal while using resources most efficiently, we will carry out the following specific Aims: Aim 1: Determination of the microsomal and plasma stability in vitro, toxicity and pharmacokinetics in animals, and antitumor activity in multiple xenograft models of human cancer for several of the most promising lead compounds. Aim 2: Elucidation, for several of the most promising Smac mimetics, of the cellular mechanism of action for apoptosis induction in cancer cells. Aim 3: Structure-based design and synthesis of new analogues based upon the most promising leads to further define the structure-activity relationship for this class of promising Smac mimetics and to identify additional new and superior analogues for in vivo studies. Aim 4: For the new analogues obtained in Aim 3, determination of the binding affinities and specificity to IAP proteins, their activity in antagonizing XIAP, their activity in cancer cell lines and selectivity over normal cells. Our preliminary data provide strong support for our central hypothesis, research design and strategy and have laid a solid foundation for the success of this project. Successfully carried out, this project will bring, at a minimum, 1-2 potent, well-characterized, highly optimized, orally active Smac mimetics into advanced preclinical development as a new class of anticancer therapy for the treatment of many types of human cancer. 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）：凋亡蛋白抑制剂（IAP）是一类关键凋亡调节剂。在这些IAP蛋白中，细胞IAP-1（CIAP-1）和细胞IAP-2（CIAP-2）在调节死亡受体受体介导的细胞凋亡中起着至关重要的作用，而X连接的IAP（XIAP）是两种死亡受体受体介导的和线粒体介导的popoptosis的核心调节剂。由于其作为凋亡调节剂的核心作用，XIAP和CIAP-1/2是有希望的癌症治疗靶标。 SMAC是这些IAP蛋白的内源性拮抗剂，并通过其AVPI四肽结合基序与它们相互作用。近年来，强烈的研究工作已致力于被称为SMAC Mimetics的小分子的设计和开发，这些分子模仿AVPI结合基序，并充当IAP蛋白的拮抗剂。 SMAC Mimetics不仅能够使癌细胞对其他治疗剂诱导凋亡诱导凋亡，而且还可以作为单个药物在体外诱导凋亡和体内诱导多种肿瘤类型的癌细胞系中有效。 SMAC Mimetics被认为具有新型抗癌药物的发展潜力。 在R01竞争的续约中，我们建议评估一种新型的有效，活跃，有希望的SMAC模拟物作为治疗人类癌症的新疗法。我们的初步数据表明，我们有希望的铅化合物与XIAP和CIAP-1/2结合，与纳摩尔范围低的亲和力结合，有效地诱导癌细胞中的凋亡，对正常细胞具有最小的毒性，并且具有高度一致的细胞作用机制，该机制与靶向IAP蛋白诱导的靶向IAP蛋白具有高度一致。我们的铅化合物之一是口服剂在诱导异种移植肿瘤组织中凋亡以及MDA-MB-231异种移植模型中肿瘤生长的抑制作用，同时在高效剂量上对动物的毒性无毒性。 我们在该项目中的最终目标是开发一种高度有效的，口服的SMAC模拟物作为治疗人类癌症的新疗法。为了最大程度地提高实现我们的最终目标的可能性，同时最有效地使用资源，我们将执行以下特定目的：目标1：确定动物中的微粒体和血浆稳定性的体外，毒性和药代动力学，以及在人类癌症的多个癌症模型中的抗肿瘤抗体活性。 AIM 2：阐明了几种最有希望的SMAC模拟物，是癌细胞凋亡诱导作用的细胞作用机理。 AIM 3：基于结构的设计和基于最有希望的新类似物的合成，导致了这类有前途的SMAC模拟物的结构活性关系，并确定体内研究的其他新的和出色的类似物。 AIM 4：对于AIM 3中获得的新类似物，确定与IAP蛋白的结合亲和力和特异性，它们在拮抗XIAP中的活性，它们在癌细胞系中的活性以及对正常细胞的选择性。 我们的初步数据为我们的中心假设，研究设计和策略提供了大力支持，并为该项目的成功奠定了坚实的基础。该项目成功地进行了成功，将至少1-2个有效，良好的，高度优化的口服SMAC Mimetics进入先进的临床前发育，作为一种新的抗癌治疗，用于治疗许多类型的人类癌症。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。