Development of Proteasome Selective Inhibitors for Cancer Therapy

项目3的总体目标是在设计小分子合成物的基础上发现新的抗癌药物。 抑制蛋白酶体的胰凝乳蛋白酶样活性的分子。蛋白酶体是一种多功能蛋白酶 复合物，负责降解蛋白质，如肿瘤抑制因子p53，细胞周期蛋白依赖性 激酶抑制剂p27和p21以及促凋亡蛋白Bax和1 KB。许多肿瘤依赖于 蛋白酶体逃避程序性细胞死亡（细胞凋亡）并生存。大多数人类癌症 具有低水平的蛋白酶体底物，如p53、p27和Bax，这与 肿瘤侵袭性强，预后差，对化疗耐药，患者生存期缩短。 项目3所基于的假设是，蛋白酶体选择性抑制剂将阻断 蛋白酶体介导促凋亡蛋白的降解，并通过以下方式抑制肿瘤生长 诱导细胞凋亡。为了验证这一假设，提出了以下具体目标：1）使用高 通量筛选（HTS）和化学文库设计以鉴定胰凝乳蛋白酶样选择性蛋白酶体 抑制剂的2)评价特定目标1中鉴别的化合物抑制 蛋白酶体胰凝乳蛋白酶样活性，并将抑制剂的效力与其诱导 细胞凋亡和细胞周期阻滞，并抑制恶性转化。为了确定蛋白酶体 抑制剂对癌细胞的选择性超过正常细胞。3)为了确定蛋白酶体抑制剂- 诱导的癌细胞凋亡是由促凋亡蛋白的积累介导的。4)以确定是否 BclXL/Bax需要抑制蛋白酶体胰凝乳蛋白酶样活性（项目4）， mdm 2/p53和/或mdmx/p53（项目1）破坏剂诱导细胞凋亡。5)评估的能力 蛋白酶体抑制剂，其选择性抑制胰凝乳蛋白酶样活性，以诱导细胞凋亡和抑制肿瘤 在使用人肿瘤异种移植物的动物模型中的生长。进行药效学、联合 治疗和毒性研究。这项研究将提供化学探针，使我们能够 增强我们对蛋白酶体如何调节异常信号转导途径的理解， IKB/NF κ B、mdm 2/p53和/或mdmx/p53和BclXL/Bax，它们对肿瘤存活/死亡至关重要。最后， 这些研究将导致发现胰凝乳蛋白酶样蛋白酶体抑制剂， 本发明的化合物具有抗肿瘤活性，并且将拓宽可以成功治疗的人类肿瘤的范围。

The overall goal of Project 3 is to discover novel anticancer drugs based on designing small synthetic molecules that inhibit the chymotrypsin-like activity of the proteasome. The proteasome is a multi-protease complex that is responsible for degrading proteins such as the tumor suppressor p53, the cyclin-dependent kinase inhibitors p27 and p21 and the proapoptotic proteins Bax and 1KB. Many tumors are dependent on the proteasome to evade programmed cell death (apoptosis) and survive. The majority of human cancers have low levels of substrates of the proteasome such as p53, p27 and Bax and this has been associated with tumor aggressiveness, poor prognosis, resistance to chemotherapy and shortened patient survival time. The hypothesis upon which Project 3 is based is that proteasome selective inhibitors will block proteasome mediated degradation of pro-apoptotic proteins, andwill suppress tumor growth by inducing apoptosis. To test this hypothesis the following specific aims are proposed: 1) To use high throughput screening (HTS) and chemical library design to identify chymotrypsin-like selective proteasome inhibitors. 2) To evaluate the potency and selectivity of the compounds identified in Specific Aim 1 to inhibit the proteasome chymotrypsin-like activity, and to correlate the inhibitors' potency to their ability to induce apoptosis and cell cycle arrest, and to inhibit malignant transformation. To determine if proteasome inhibitors are selective for cancer cells over normal cells. 3) To determine whether proteasome inhibitor- induced cancer cell apoptosis is mediated by accumulation of pro-apoptotic protein. 4) To determine if suppression of the proteasome chymotrypsin-like activity is required for BclXL/Bax (Project 4), and mdm2/p53 arid/or mdmx/p53 (Project 1) disrupters to induce apoptosis. 5) To evaluate the ability of proteasome inhibitors, that selectively inhibit chymotrypsin-like activity, to induce apoptosis and inhibit tumor growth in animal models using human tumor xenografts. To carry out pharmacodynamic, combination therapy and toxicity studies. The studies proposed will provide the chemical probes that will allow us to enhance our understanding of how the proteasome regulates aberrant signal transduction pathways such as IKB/NFKB, mdm2/p53 and/or mdmx/p53 and BclXL/Bax that are critical to tumor survival/death. Ultimately, the studies will lead to the discovery of chymotrypsin-like proteasome inhibitors with proapoptotic and antitumor activities, and will broaden the spectrum of human tumors that can be successfully treated.