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: 8212468
• 负责人: Michael Chorev
• 金额: $ 18.48万
• 依托单位: HARVARD MEDICAL SCHOOL
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212468
• 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）：翻译起始位于许多明确的致癌、促凋亡和肿瘤抑制途径的顶点，这使其成为开发抗癌剂的有吸引力的靶标，并代表了癌症治疗的新范式。由于翻译控制的恢复下调致癌蛋白，对管家蛋白的影响最小，翻译起始的小分子抑制剂具有实现宽治疗窗的极好潜力。翻译起始抑制剂作为一类新的抗癌药物的出现与当前的观点一致，即现代抗癌治疗必须是靶向特异性的，并且抑制癌细胞而不是正常细胞的生长，这与仍然流行的遗传毒性治疗有明显区别。该提案的目标是对#4EGI-1（一种噻唑基-腙丙酸（THPA）衍生物）进行命中-先导优化，以获得有效和选择性的临床前先导候选药物。在我们的实验室中通过化学文库的高通量筛选鉴定的#4EGI-1抑制eIF 4 E/eIF 4G相互作用，该相互作用对于形成eIF 4F复合物（翻译起始级联中的关键调节步骤）是帽依赖性翻译的抑制剂。基于结构的优化将结合联合收割机从NMR和对接研究中获得的见解，这些研究产生了eIF 4 E-#4EGI-1复合物的模型，初步的药物化学，其鉴定了推定的药效团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eIF 4 E的竞争性结合，2.抑制癌细胞生长，3.下拉实验以证明eIF 4F复合物的破坏，以及4.细胞提取物中帽依赖性翻译的抑制，以及人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3位取代基以及噻唑烷环4位和5位取代基的集中文库，旨在增强与eIF 4 E上热点和推定外位点的相互作用。此外，我们将使THPA支架刚性化以将其锁定在环外C=N周围的E或Z构型中，以防止自发异构化，从而表征生物活性构型。总之，我们的努力将导致开发一种有效的和选择性的临床前抗癌候选药物，靶向eIF 4F复合物。 公共卫生部门：翻译起始位于许多明确的致癌、促凋亡和肿瘤抑制途径的顶点，这使其成为开发抗癌剂的有吸引力的靶标，并代表了癌症治疗的新范式。由于翻译控制的恢复下调致癌蛋白，对管家蛋白的影响最小，翻译起始的小分子抑制剂具有实现宽治疗窗的极好潜力。我们计划对eIF 4 E/eIF 4G相互作用的小分子抑制剂#4EGI-1进行命中-先导优化，这是翻译起始级联反应中的关键参与者，以鉴定有效和选择性的临床前候选物。