Development of Translation Initiation Inhibitors and their Anti-Cancer Activity

翻译起始抑制剂的开发及其抗癌活性

• 批准号: 8501898
• 负责人: Michael Chorev
• 金额: $ 16.47万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501898
• 关键词: Accreditation; Acute; Affect; Affinity; Anchorage-Independent Growth; Animal Model; Antineoplastic Agents; Apoptotic; Azides; Binding; Biological Assay; Biological Availability; Breast Carcinoma; Cancer Cell Growth; Cell Extracts; Cells; Cessation of life; Chemicals; Clinical; Clonal Expansion; Competitive Binding; Complex; Computer Simulation; Development; Dissociation; Docking; Dose; Drug Kinetics; Ectopic Expression; Epithelial Cells; Fluorescence; Fluorescence Polarization; Goals; Growth Factor; Health; Hot Spot; Housekeeping; Housing; Human; Hybrids; Hydrazones; In Vitro; Individual; Inhibition of Cancer Cell Growth; Isomerism; Laboratories; Lead; Libraries; Ligand Binding; Ligands; Location; Maintenance; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mammary gland; Maximum Tolerated Dose; Measurement; Messenger RNA; Methods; Modeling; Modification; Molecular; Molecular Conformation; Molecular Models; Molecular and Cellular Biology; Morbidity - disease rate; Normal Cell; Oncogenic; Pathway interactions; Peptide Initiation Factors; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Phosphorylation Site; Physiological; Plasma; Play; Positioning Attribute; Preclinical Drug Evaluation; Propionic Acids; Proteins; RNA Cap-Binding Proteins; Recurrence; Research Proposals; Risk; Roentgen Rays; Role; Scaffolding Protein; Specificity; Structure; Structure-Activity Relationship; Testing; Therapeutic; Time; Toxic effect; Translation Initiation; Translations; Triazoles; Tumor Suppressor Proteins; Tumorigenicity; Xenograft Model; Xenograft procedure; base; cancer therapy; combinatorial; design; drug candidate; drug development; efficacy testing; follow-up; helicase; high throughput screening; human cancer mouse model; in vitro Assay; in vivo; inhibitor/antagonist; insight; malignant phenotype; mimetics; molecular modeling; mortality; multidisciplinary; mutant; novel; overexpression; pharmacophore; pre-clinical; prevent; programs; quantum; research study; restoration; scaffold; small molecule; small molecule libraries; tool; tumor growth

DESCRIPTION (provided by applicant): The location of translation initiation at the apex of many well-defined oncogenic, pro-apoptotic and tumor-suppressor pathways makes it an attractive target for the development of anti-cancer agents and represents a new paradigm in cancer therapy. Because restoration of translational control down-regulates oncogenic proteins with minimal effect on housekeeping proteins, small molecule inhibitors of translation initiation have excellent potential for achieving a wide therapeutic window. The emergence of translation initiation inhibitors as a new class of anticancer drugs is consistent with the current view that modern anti-cancer therapy must be target-specific and inhibit the growth of cancer cells but not of normal cells, a distinct difference from still-prevalent genotoxic therapies. The goal of this proposal is to execute a hit-to-lead optimization of #4EGI-1, a thiazolyl-hydrazone propionic acid (THPA) derivative to obtain a potent and selective preclinical lead candidate. The #4EGI-1, identified in our laboratories by high throughput screening of chemical libraries inhibits eIF4E/eIF4G interaction that is essential for the formation of eIF4F complex (a critical regulatory step in the translation initiation cascade) is an inhibitor of cap-dependent translation. The structure-based optimization will combine insights gained from the NMR- and docking studies that resulted in a model of eIF4E-#4EGI-1 complex, preliminary medicinal chemistry that identified the putative pharmacophore and performed a limited structure-activity relationship studies, a panel of in vitro assays that include: 1. competitive binding to eIF4E, 2. inhibition of cancer cell growth, 3. pull-down experiment to demonstrate disruption of eIF4F complex, and 4. inhibition of cap dependent translation in cell extracts, and a xenograft mouse model of human cancer. Our integrative and iterative strategy will include two tier elaboration of the THPA scaffold. Initially, we will design focused libraries directed toward the substituent at position 3 of the propionic acid, and positions 4 and 5 of the thiazolidine ring aiming to enhance interaction with the hot spot and putative exosites on eIF4E. In addition, we will rigidify the THPA scaffold to lock it in either E or Z configuration around the exocyclic C=N in order to prevent spontaneous isomerization thus characterizing the bioactive configuration. Taken together, our effort will lead to the development of a potent and selective preclinical anti-cancer drug candidate targeting the eIF4F complex. PUBLIC HEALTH REVELANCE: The location of translation initiation at the apex of many well-defined oncogenic, pro-apoptotic and tumor- suppressor pathways makes it an attractive target for the development of anti-cancer agents and represents a new paradigm in cancer therapy. Because restoration of translational control down-regulates oncogenic proteins with minimal effect on housekeeping proteins, small molecule inhibitors of translation initiation have excellent potential for achieving a wide therapeutic window. We plan to carry out a hit-to-lead optimization of #4EGI-1 a small molecule inhibitor of eIF4E/eIF4G interaction, which is a crucial player in the translation initiation cascade, in an effort to identify a potent and selective preclinical candidate.

描述（由申请人提供）：翻译起始位置位于许多明确的致癌、促凋亡和肿瘤抑制途径的顶端，这使其成为抗癌药物开发的有吸引力的目标，并代表了癌症治疗的新范例。由于翻译控制的恢复下调致癌蛋白，而对管家蛋白的影响最小，因此翻译起始的小分子抑制剂具有实现宽治疗窗的巨大潜力。翻译起始抑制剂作为一类新型抗癌药物的出现，与当前的观点一致，即现代抗癌治疗必须具有靶点特异性，抑制癌细胞而不是正常细胞的生长，这与仍然流行的基因毒性疗法有明显区别。该提案的目标是对 #4EGI-1（一种噻唑基腙丙酸 (THPA) 衍生物）执行从命中到先导的优化，以获得有效且选择性的临床前先导候选药物。我们实验室通过高通量筛选化学文库鉴定出的 #4EGI-1 可抑制 eIF4E/eIF4G 相互作用，这对于 eIF4F 复合物（翻译起始级联中的关键调控步骤）的形成至关重要，是帽依赖性翻译的抑制剂。基于结构的优化将结合从 NMR 和对接研究中获得的见解，这些研究产生了 eIF4E-#4EGI-1 复合物模型、识别推定药效基团的初步药物化学并进行了有限的结构-活性关系研究，一组体外测定包括：1. 与 eIF4E 的竞争性结合，2. 抑制癌细胞生长，3. 下拉实验以证明 eIF4F 复合物的破坏，以及 4. 细胞提取物中帽子依赖性翻译的抑制，以及人类癌症的异种移植小鼠模型。我们的综合和迭代策略将包括 THPA 支架的两层阐述。最初，我们将设计针对丙酸位置 3 以及噻唑烷环位置 4 和位置 5 的取代基的重点文库，旨在增强与 eIF4E 上热点和推定外部位点的相互作用。此外，我们将刚性化 THPA 支架，将其锁定在环外 C=N 周围的 E 或 Z 构型，以防止自发异构化，从而表征生物活性构型。总而言之，我们的努力将导致开发一种针对 eIF4F 复合物的有效且选择性的临床前抗癌候选药物。 公众健康启示：翻译起始位置位于许多明确的致癌、促凋亡和肿瘤抑制途径的顶端，这使其成为抗癌药物开发的有吸引力的目标，并代表了癌症治疗的新范例。由于翻译控制的恢复下调致癌蛋白，而对管家蛋白的影响最小，因此翻译起始的小分子抑制剂具有实现宽治疗窗的巨大潜力。我们计划对#4EGI-1（一种 eIF4E/eIF4G 相互作用的小分子抑制剂，它是翻译起始级联中的关键参与者）进行从命中到先导的优化，以努力确定一种有效的、选择性的临床前候选药物。

项目成果

Structure-activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein-protein interaction inhibitors.

• DOI: 10.1016/j.ejmech.2014.03.034
• 发表时间: 2014-04-22
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: Takrouri K;Chen T;Papadopoulos E;Sahoo R;Kabha E;Chen H;Cantel S;Wagner G;Halperin JA;Aktas BH;Chorev M
• 通讯作者: Chorev M