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: 8034268
• 负责人: SAID M SEBTI
• 金额: $ 193.07万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034268
• 关键词: Targeting; Signal; Transduction; Pathways; Cancer

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）：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组成部分被过度激活，包括磷酸酶SHP2和GTPase Ras，它们激活丝氨酸/苏氨酸激酶Raf，进而结合、磷酸化和灭活肿瘤抑制因子pRb。信号转导的其他异常成分是那些允许肿瘤逃避凋亡的成分，包括通过结合癌蛋白mdm2使肿瘤抑制因子p53失活，抗凋亡Bel蛋白过表达，蛋白酶体持续降解促凋亡蛋白Baxand 1KB。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。本项目所基于的中心假设是，破坏mdm2/p53、Raf/Rb和Bcl/Bax的关联，抑制SHP2和蛋白酶体的活性，会诱导人类癌细胞凋亡，抑制恶性转化和肿瘤生长。五个高度整合和相互关联的项目和三个核心将非常密切地合作，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（项目3）和SHP2（项目5）的抑制剂。来自所有5个项目的生物学家将对这些筛选结果以及来自市售化学文库的HTS结果进行效价和选择性评估。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物优化。在动物模型中，我们将评估这些高效和选择性先导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。我们的药物发现过程的每一步，从组合文库的设计和合成，到特定生化和分子分析的设计，动物抗肿瘤活性的评估将高度集中在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理学药物的创造上。此外，一个项目对一个途径具有高度选择性的化合物的鉴定将被其他项目用于确定异常途径之间串扰的重要性以及每个途径单独和集体对恶性转化的贡献。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，并最终将导致发现新的抗癌药物，从而拓宽可成功治疗的人类癌症的范围。

项目成果

Selective disruption of rb-raf-1 kinase interaction inhibits pancreatic adenocarcinoma growth irrespective of gemcitabine sensitivity.

无论吉西他滨敏感性如何，选择性破坏 rb-raf-1 激酶相互作用都会抑制胰腺腺癌的生长。

• DOI: 10.1158/1535-7163.mct-12-0719
• 发表时间: 2013
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Treviño,JoséG;Verma,Monika;Singh,Sandeep;Pillai,Smitha;Zhang,Dongyu;Pernazza,Daniele;Sebti,SaidM;Lawrence,NicholasJ;Centeno,BarbaraA;Chellappan,SrikumarP
• 通讯作者: Chellappan,SrikumarP

Efficient assembly of 2,5,6-substituted pyrimidines via MgI(2)-mediated Morita-Baylis-Hillman reaction.

通过 MgI(2) 介导的 Morita-Baylis-Hillman 反应有效组装 2,5,6-取代的嘧啶。

• DOI: 10.1021/cc100001e
• 发表时间: 2010
• 期刊: Journal of combinatorial chemistry
• 作者: Sharma,Vasudha;McLaughlin,MarkL
• 通讯作者: McLaughlin,MarkL

Achieving cell penetration with distance-matching cysteine cross-linkers: a facile route to cell-permeable peptide dual inhibitors of Mdm2/Mdmx.

• DOI: 10.1039/c1cc13320a
• 发表时间: 2011-09-07
• 期刊: Chemical communications (Cambridge, England)
• 作者: Muppidi A;Wang Z;Li X;Chen J;Lin Q
• 通讯作者: Lin Q

Facile iterative synthesis of 2,5-terpyrimidinylenes as nonpeptidic alpha-helical mimics.

轻松迭代合成 2,5-三联嘧啶亚基作为非肽 α 螺旋模拟物。

• DOI: 10.1021/jo100272d
• 发表时间: 2010
• 期刊: The Journal of organic chemistry
• 作者: Anderson,Laura;Zhou,Mingzhou;Sharma,Vasudha;McLaughlin,JillianM;Santiago,DanielN;Fronczek,FrankR;Guida,WayneC;McLaughlin,MarkL
• 通讯作者: McLaughlin,MarkL

Going beyond Binary: Rapid Identification of Protein-Protein Interaction Modulators Using a Multifragment Kinetic Target-Guided Synthesis Approach.

• DOI: 10.1021/acs.jmedchem.3c00108
• 发表时间: 2023-04-13
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Nacheva, Katya;Kulkarni, Sameer S.;Kassu, Mintesinot;Flanigan, David;Monastyrskyi, Andrii;Iyamu, Iredia D.;Doi, Kenichiro;Barber, Megan;Namelikonda, Niranjan;Tipton, Jeremiah D.;Parvatkar, Prakash;Wang, Hong-Gang;Manetsch, Roman
• 通讯作者: Manetsch, Roman