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）：该项目申请的总体长期目标是发现基于破坏异常信号转导途径的治疗癌症的新药。在人类癌症中，信号转导途径的许多成分都被过度激活，包括磷酸酶 SHP2 和 GTPase Ras，它们激活丝氨酸/苏氨酸激酶 Raf，而 Raf 反过来又结合、磷酸化肿瘤抑制因子 pRb 并使肿瘤抑制因子 pRb 失活。信号转导的其他异常成分是那些允许肿瘤逃避细胞凋亡的成分，包括通过结合癌蛋白 mdm2 使肿瘤抑制因子 p53 失活、抗凋亡 Bel 蛋白过度表达，以及促凋亡蛋白 Baxand 1KB 持续降解。蛋白酶体。这些异常的信号转导途径与肿瘤发生密切相关，并与不良预后、化疗耐药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，破坏 mdm2/p53、Raf/Rb 和 Bcl/Bax 关联以及抑制 SHP2 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。五个高度集成且相互关联的项目和三个核心将紧密合作，共同实现 P01 的总体目标。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文库，并通过高通量筛选 (HTS) 核心进行评估，以识别 mdm2/p53（项目 1）、Raf/Rb（项目 2）和 Bcl 的干扰物/Bax（项目 4）以及蛋白酶体抑制剂（项目 3）和 SHP2（项目 5）。来自所有 5 个项目的生物学家将评估来自这些筛选的命中以及来自市售化学库的 HTS 的命中的效力和选择性。这些结构活性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。然后将评估高效和选择性的先导化合物在动物模型中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。我们的药物发现过程的每一步（从组合的设计和合成）文库、特定生化和分子测定的设计以及动物抗肿瘤活性的评估将高度关注于开发对具有异常激活的特定*信号转导途径的人类癌症具有最高选择性的药物。此外，一个项目对一种途径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。本 P01 申请中描述的工作将增强我们对 SHP2、蛋白酶体、Bcl/Bax、Raf/Rb 和 mdm2/p53 在肿瘤发生中的作用的理解，并最终发现新型抗癌药物，从而拓宽人类抗癌谱。可以成功治疗的癌症。