The IAP BIR Domain: A Novel Target for Cancer Therapy

描述：(申请人提供) 除了癌细胞无限的增殖潜力外， 肿瘤生长和转移的第二个重要因素是 以避免癌细胞的凋亡。这一特征还可能 对化疗的抗药性是其根本原因。细胞凋亡在血管紧张性疾病中的生理作用 杀死功能异常的细胞可以通过以下方式在癌细胞中被颠覆 影响细胞凋亡途径中关键蛋白的基因损伤，如Bcl2 和P53。近年来，一个重要的细胞凋亡抑制因子家族--AIP家族 已经被发现了。这些蛋白质可能过度表达，或者 在肿瘤细胞中上调，有助于抵抗细胞凋亡。目标是 目前的建议是发现IAP的小分子拮抗剂 通过抑制IAP的BIR域起作用的功能。抑制力 BiR结构域可能产生具有广泛抗癌活性但作用不大的药物 在正常组织上。这些化合物将用于验证IAP的拮抗作用 将BIR抑制作为治疗癌症的靶点。此外，他们还将为 作为开发新的癌症治疗方法的起点。小的 使用一种专利药物将很快发现分子抑制剂 发现技术(TRAP)，并在无细胞、基于细胞和体内进行分析 建立它们的促凋亡和抗肿瘤活性的系统。 建议的商业应用： 可用于验证BIR抑制作为一种成功的方法的化合物 癌症治疗。铅化合物促进了新型癌症化疗药物的发现。

DESCRIPTION: (provided by applicant) In addition to the unlimited potential of cancer cells for proliferation, a second important contributor to tumor growth and metastasis is the ability of cancer cells to avoid apoptotic cell death. This characteristic may also underlie resistance to chemotherapy. The physiological role of apoptosis in killing abnormally functioning cells can be subverted in cancer cells through genetic lesions that affect key proteins in apoptotic pathways, such as Bcl-2 and p53. Recently, an important family of apoptosis inhibitors, the AIP family of proteins, has been discovered. These proteins may be over expressed, or upregulated, in tumor cells, contributing to resistance to apoptosis. The goal of the present proposal is to discover small molecule antagonists of IAP function that act by inhibiting the BIR domain of the IAP. Inhibition of the BIR domain may produce agents with broad anticancer activity but little effect on normal tissues. These compounds will be used to validate IAP antagonism by BIR inhibition as a target for treating cancer. In addition, they will serve as a starting point for the development of novel cancer therapeutics. Small molecule inhibitors will be rapidly discovered using a proprietary drug discovery technology (TRAP) and profiled in cell-free, cell-based, and in vivo systems to establish their pro-apoptotic and anti-tumor activities. PROPOSED COMMERCIAL APPLICATION: Compounds that can be used to validate BIR inhibition as a successful approach to cancer treatment. Lead compounds the the discovery of novel cancer chemotherapeutics.