Development of Translation Initiation Inhibitors and their Anti-Cancer Activity

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端，使其成为抗癌药物开发的一个有吸引力的靶点，代表了癌症治疗的新范式。由于翻译控制的恢复下调了致癌蛋白，而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口的极好潜力。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，这与仍然流行的基因毒性治疗有明显区别。本提案的目标是对#4EGI-1（一种噻唑酰腙丙酸（THPA）衍生物）进行hit-to-lead优化，以获得一种有效的、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发现的#4EGI-1抑制eIF4E/eIF4G相互作用，这对eIF4F复合物的形成至关重要（翻译起始级联的关键调控步骤），是帽依赖翻译的抑制剂。基于结构的优化将结合从核磁共振和对接研究中获得的见解，这些研究产生了eIF4E-#4EGI-1复合物的模型，初步的药物化学鉴定了假定的药效团，并进行了有限的结构-活性关系研究，一组体外分析包括：1。2.与eIF4E竞争性结合；2 .抑制癌细胞生长；3 .下拉实验证明eIF4F复合物的破坏；细胞提取物中帽依赖翻译的抑制作用，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。首先，我们将针对丙酸的3位取代基、噻唑烷环的4位和5位设计重点文库，旨在增强与eIF4E上热点和推测的外源位点的相互作用。此外，我们将硬化THPA支架，使其锁定在外环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。总之，我们的努力将导致开发一种针对eIF4F复合物的有效和选择性的临床前抗癌候选药物。公共卫生启示：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端，使其成为抗癌药物开发的一个有吸引力的靶点，并代表了癌症治疗的新范式。由于翻译控制的恢复下调了致癌蛋白，而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口的极好潜力。我们计划对eIF4E/eIF4G相互作用的小分子抑制剂#4EGI-1进行hit-to-lead优化，该抑制剂在翻译起始级联中起关键作用，以努力确定一种有效的、选择性的临床前候选药物。

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.