Targeting Signal Transduction Pathways for Cancer Drug Discovery

描述（申请人提供）：本项目申请的总体长期目标是发现基于破坏异常信号转导通路的治疗癌症的新药。在人类癌症中，信号转导途径的许多组分被过度活化，包括磷酸酶SHP 2和GT3 Ras，其活化丝氨酸/苏氨酸激酶Raf，其进而结合、磷酸化和失活肿瘤抑制因子pRb。异常的信号转导的其他组分是允许肿瘤逃避细胞凋亡的那些，包括通过结合癌蛋白mdm 2使肿瘤抑制因子p53失活，抗细胞凋亡Bel蛋白的过表达，以及蛋白酶体对促细胞凋亡蛋白p53和1 KB的持续降解。这些异常的信号转导通路与肿瘤发生密切相关，并与预后不良、化疗耐药和患者生存时间缩短有关。该项目的中心假设是，破坏mdm 2/p53、Raf/Rb和Bcl/Bax相关性以及抑制SHP 2和蛋白酶体活性将诱导细胞凋亡并抑制人类癌细胞的恶性转化和肿瘤生长。五个高度集成和相互关联的项目和三个核心将密切合作，以实现P01的总体目标。每个项目的化学家将使用基于结构的合理设计来制备化学文库，这些文库将通过高通量筛选（HTS）核心进行评估，以鉴定mdm 2/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（项目3）和SHP 2（项目5）的抑制剂。来自这些筛选的命中以及来自市售化学文库的HTS的命中将由来自所有5个项目的生物学家评价效价和选择性。这些构效关系研究的结果将反馈给所有5个项目的化学家进行先导化合物优化。然后，将在动物模型中评估高度有效和选择性的先导化合物抑制特定信号传导途径、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，从设计和合成组合文库，设计特定的生物化学和分子测定，在动物中评价抗肿瘤活性将高度集中于产生对具有异常激活的特异性信号转导途径的人类癌症具有最高程度选择性的药理学试剂。此外，通过一个项目鉴定对一种途径具有高度选择性的化合物将被其他项目用于确定异常途径之间的串扰的重要性以及每种途径单独和共同对恶性转化的贡献。P01申请中描述的工作将增强我们对SHP 2，蛋白酶体，Bcl/Bax，Raf/Rb和mdm 2/p53在肿瘤发生中的作用的理解，并最终导致发现新的抗癌药物，这将扩大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.