Targeting Signal Transduction Pathways for Cancer Drug Discovery

描述(由申请人提供)：该计划项目申请的总体长期目标是基于干扰异常信号转导通路发现治疗癌症的新药。在人类癌症中，信号转导通路的许多成分都被过度激活，包括磷酸酶SHP2和GTP酶RAS，它们激活丝氨酸/苏氨酸激酶Raf，进而结合、磷酸化和失活肿瘤抑制因子pRb。其他异常的信号转导成分包括那些允许肿瘤逃避凋亡的成分，包括通过结合癌蛋白MDM2而使抑癌基因P53失活，过表达抗凋亡的Bel蛋白，以及蛋白酶体持续降解促凋亡蛋白Bax1和1KB。这些异常的信号转导通路与肿瘤的发生密切相关，并与预后不良、化疗耐药和患者生存时间缩短有关。这个项目所基于的中心假设是，破坏MDM2/P53、Raf/Rb和BclBax的关联，抑制SHP2和蛋白酶体的活性，将诱导人类癌细胞凋亡，并抑制肿瘤的恶性转化和生长。5个高度一体化和相互关联的项目和3个核心将非常密切地合作，以实现P01的总目标。每个项目的化学家将使用基于结构的合理设计来准备化学文库，这些文库将由高通量筛选(HTS)核心进行评估，以确定MDM2/P53(项目1)、Raf/Rb(项目2)和Bcl/Bax(项目4)的干扰物以及蛋白酶体的抑制物(项目3)和SHP2(项目5)。所有5个项目的生物学家将对来自这些屏幕的命中以及HTS商业可用化学库的命中进行有效性和选择性的评估。这些结构活性关系研究的结果将被反馈给所有5个项目的化学家，以进行先导优化。在动物模型中，我们将评估这些高效和选择性的先导化合物抑制特定信号通路、细胞增殖和恶性转化、促进细胞凋亡和抑制肿瘤生长的机制。我们药物发现过程的每一步，从组合文库的设计和合成、特定生化和分子检测的设计，到动物抗肿瘤活性的评估，都将高度集中于创造对具有异常激活的特定*信号转导通路的人类癌症具有最高选择性的药理制剂。此外，一个项目对一条途径具有高度选择性的化合物的鉴定将被其他项目用来确定异常途径之间的串扰的重要性，以及每条途径单独和共同对恶性转化的贡献。在这份P01申请中描述的工作将加深我们对SHP2、蛋白酶体、Bcl/Bax、Raf/Rb和MDM2/P53在肿瘤发生中的作用的理解，并最终将导致新的抗癌药物的发现，这将拓宽可以成功治疗的人类癌症的范围。

DESCRIPTION (provided by applicant): The overall long-term goal of this program project application is to discover novel drugs for the treatment of cancer based on disrupting aberrant signal transduction pathways. In human cancers many components of signal transduction pathways are hyperactivated including the phosphatase SHP2 and the GTPase Ras which activate the serine/threonine kinase Raf which in turn binds, phosphorylates and inactivates the tumor suppressor pRb. Other components of signal transduction that are aberrant are those that allow tumors to evade apoptosis and include inactivation of the tumor suppressor p53 by binding the oncoprotein mdm2, overexpression of the anti-apoptotic Bel proteins, and sustained degradation of the proapoptotic proteins Baxand 1KB by the proteasome. These aberrant signal transduction pathways are intimately involved in oncogenesis and have been associated with poor prognosis, resistance to chemotherapy and shortened patient survival time. The central hypothesis upon which this program project is based is that disruption of mdm2/p53, Raf/Rb and Bcl/Bax associations and inhibition of SHP2 and proteasome activities will induce apoptosis and inhibit malignant transformation and tumor growth in human cancer cells. Five highly integrated and interrelated projects and 3 cores will work very closely together towards the overall goal of the P01. Chemists from each project will use structure-based rational design to prepare chemical libraries that will be evaluated by the high throughput screening (HTS) core to identify disrupters of mdm2/p53 (Project 1), Raf/Rb (Project 2), and Bcl/Bax (Project 4) and inhibitors of the proteasome (Project 3) and SHP2 (Project 5). Hits from these screens as well as those from HTS of commercially available chemical libraries will be evaluated by biologists from all 5 projects for potency and selectivity. The results from these structure activity relationship studies will then be fed back to the chemists of all 5 projects for lead optimization. The highly potent and selective leads will then be evaluated for the mechanism by which they inhibit specific signaling pathways, cell proliferation and malignant transformation, promote apoptosis and suppress tumor growth in animal models, Every step of our drug discovery process from design and synthesis of combinatorial libraries, design of specific biochemical and molecular assays, to evaluation of antitumor activity in animals will be highly focused on the creation of pharmacological agents with the highest degree of selectivity towards human cancers with aberrantly activated specific* signal transduction pathways. Furthermore, identification by one project of compounds that are highly selective for one pathway will be used by other projects to determine the importance of crosstalk between the aberrant pathways and the contribution of each pathway alone and collectively to malignant transformation. The work described in this P01 application will enhance our understanding of the role of SHP2, proteasome, Bcl/Bax, Raf/Rb and mdm2/p53 in oncogenesis and ultimately will result in the discovery of novel anticancer drugs that will broaden the spectrum of human cancers that can be treated successfully.