Design of Orally Bioavailable IAP Antagonists for Cancer Treatment

描述（由申请人提供）：凋亡抑制蛋白（IAP）是一类关键的凋亡调节因子。在这些IAP蛋白中，细胞IAP-1（cIAP-1）和细胞IAP-2（cIAP-2）在死亡受体介导的细胞凋亡的调节中起关键作用，并且X连锁IAP（XIAP）是死亡受体介导的细胞凋亡途径和细胞凋亡途径的中心调节剂。由于其作为细胞凋亡调节剂的核心作用，XIAP和cIAP-1/2是有前途的癌症治疗靶点。 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，大量的研究工作致力于设计和开发称为Smac模拟物的小分子，其模拟AVPI结合基序并作为IAP蛋白的拮抗剂发挥作用。Smac模拟物不仅能够使癌细胞对其它治疗剂诱导的细胞凋亡敏感，而且在不同肿瘤类型的癌细胞系的亚组中作为单一药剂在体外和体内诱导细胞凋亡中是有效的。Smac模拟物被认为是一类具有巨大发展潜力的新型抗肿瘤药物。 在R 01竞争更新中，我们建议评估一类新的强效，口服活性，有前途的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，我们有前途的先导化合物结合XIAP和cIAP-1/2的亲和力在低纳摩尔范围内，有效地诱导癌细胞凋亡，具有最小的毒性正常细胞，并具有细胞作用机制高度一致的目标IAP蛋白诱导凋亡。我们的先导化合物之一作为口服药剂在异种移植肿瘤组织中诱导细胞凋亡和在MDA-MB-231异种移植模型中抑制肿瘤生长方面是高度有效的，同时在高度有效剂量下对动物没有显示出毒性。 我们在这个项目中的最终目标是开发一种高效的，口服活性的Smac模拟物作为治疗人类癌症的新疗法。为了最大限度地实现我们的最终目标，同时最有效地利用资源的可能性，我们将进行以下具体目标：目标1：确定微粒体和血浆的体外稳定性，毒性和动物药代动力学，以及在多种异种移植模型的人癌症的抗肿瘤活性的几个最有前途的先导化合物。目的2：阐明几种最有前途的Smac模拟物在癌细胞中诱导凋亡的细胞作用机制。目标3：基于结构的设计和合成新的类似物的基础上最有前途的导致进一步定义的结构-活性关系，这类有前途的Smac模拟物，并确定额外的新的和上级类似物的体内研究。目标4：对于在目的3中获得的新类似物，测定对IAP蛋白的结合亲和力和特异性、它们拮抗XIAP的活性、它们在癌细胞系中的活性和相对于正常细胞的选择性。 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强有力的支持，为该项目的成功奠定了坚实的基础。该项目的成功实施将至少带来1-2种有效的，充分表征的，高度优化的，口服活性的Smac模拟物进入高级临床前开发，作为一类新的抗癌疗法，用于治疗多种类型的人类癌症。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预后。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。

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.