Targeting Signal Transduction Pathways for Cancer Drug Discovery

针对癌症药物发现的信号转导途径

• 批准号: 7759306
• 负责人: SAID M SEBTI
• 金额: $ 8.62万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-05 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7759306
• 关键词: Animal Model; Animals; Antineoplastic Agents; Apoptosis; Apoptotic; Back; Binding; Biochemical; Biological Assay; Cell Proliferation; Combinatorial Synthesis; Evaluation; Goals; Guanosine Triphosphate Phosphohydrolases; Human; Lead; Libraries; Malignant - descriptor; Malignant Neoplasms; Molecular; Non-Receptor Type 11 Protein Tyrosine Phosphatase; Oncogene Proteins; PTPN11 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Process; Proteasome Inhibitor; Protein p53; Protein-Serine-Threonine Kinases; Proteins; Resistance; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Structure; Structure-Activity Relationship; Time; Tumor Suppressor Proteins; Work; base; cancer cell; cancer therapy; chemotherapy; design; drug discovery; feeding; high throughput screening; multicatalytic endopeptidase complex; novel; outcome forecast; overexpression; programs; small molecule libraries; tumor; tumor growth; tumorigenesis

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.

描述（由申请人提供）：该计划项目应用程序的总体长期目标是发现基于破坏异常信号转导途径的癌症治疗的新型药物。在人类癌症中，信号转导途径的许多组成部分都过度活化，包括磷酸酶SHP2和GTPase RA，激活丝氨酸/苏氨酸激酶RAF，而丝氨酸/苏氨酸激酶RAF反过来又结合，磷酸化并灭活肿瘤抑制剂PR。信号转导的其他成分是那些允许肿瘤逃避凋亡并通过结合癌蛋白MDM2，抗凋亡BEL蛋白的过表达以及对蛋白质蛋白质蛋白质baxand baxand baxand baxand baxand byeaseme的持续降解来避免肿瘤抑制p53的那些组成部分。这些异常的信号转导途径与肿瘤发生密切相关，并且与预后不良，对化学疗法的抵抗力和缩短患者生存时间有关。该计划项目所基于的中心假设是，MDM2/p53，RAF/RB和BCL/BAX关联的破坏以及SHP2和蛋白酶体活动的抑制作用将诱导人类癌细胞中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3个核心将非常紧密地朝着P01的整体目标努力。每个项目的化学家将使用基于结构的理性设计来准备化学库，这些化学库将通过高吞吐量筛选（HTS）核心评估，以识别MDM2/p53（项目1），RAF/RB（项目2）和BCL/BAX（项目4）（项目4）和Proteasemome（Project 3）和SHP2（Project 5）（Project 4）和抑制剂（Project 2）和抑制剂（项目4）和SHP2（Project 3）（项目5）的疾病。这些屏幕的命中以及商业化学图书馆的HTS的命中率将由所有5个项目的生物学家评估，以提高效力和选择性。然后，这些结构活动关系研究的结果将被馈回所有5个项目的化学家，以进行铅优化。 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对具有异常激活的特异性*信号转导途径的人类癌症选择性最高的药物。此外，其他项目将使用一个高度选择性的化合物识别，以确定异常途径之间的串扰的重要性以及单独使用每个途径的贡献和统称对恶性转化的贡献。在本P01应用中描述的工作将增强我们对SHP2，蛋白酶体，BCL/BAX，RAF/RB和MDM2/p53在造成发生中的作用的理解，并最终将发现新型抗癌药物，从而扩大可以成功治疗的人类癌症的光谱。