Development of Translation Initiation Inhibitors and their Anti-Cancer Activity

描述(申请人提供)：在许多明确定义的致癌、促凋亡和肿瘤抑制通路的顶端，翻译起始的位置使其成为抗癌药物开发的一个有吸引力的目标，并代表了癌症治疗的新范式。由于翻译控制的恢复会下调致癌蛋白，而对管家蛋白的影响很小，因此翻译起始的小分子抑制剂具有实现广泛治疗窗口的良好潜力。翻译起始抑制药作为一类新的抗癌药物的出现与当前的观点是一致的，即现代抗癌治疗必须是靶向性的，抑制癌细胞的生长，而不是正常细胞的生长，这与仍然流行的基因毒性疗法截然不同。这项建议的目标是对#4EGI-1进行点击到领先的优化，#4EGI-1是一种噻唑基肼丙酸(THPA)衍生物，以获得有效和选择性的临床前候选药物。我们实验室通过高通量筛选化学文库确定的#4EGI-1抑制eIF4E/eIF4G相互作用，而eIF4E/eIF4G相互作用是形成eIF4F复合体(翻译起始级联反应中的关键调控步骤)所必需的，它是帽依赖翻译的抑制因子。这种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复合体的模型，初步的药物化学确定了假定的药效团并进行了有限的构效关系研究，一系列体外试验包括：1.与eIF4E的竞争结合，2.抑制癌细胞生长，3.下拉实验证明eIF4F复合体的破坏，以及4.抑制细胞提取物中帽子依赖的翻译，以及人类癌症的异种移植小鼠模型。我们的综合和迭代战略将包括THPA脚手架的两个层次的细化。最初，我们将设计针对丙酸第3位取代基和噻唑烷环4和5位取代基的聚焦文库，旨在加强与eIF4E上的热点和推测的外切点的相互作用。此外，我们还将对THPA支架进行刚性处理，将其锁定在外环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。综上所述，我们的努力将导致开发一种针对eIF4F复合体的有效和选择性的临床前抗癌候选药物。公共卫生评论：在许多明确的致癌、促凋亡和肿瘤抑制通路的顶端，翻译起始的位置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会下调致癌蛋白，而对管家蛋白的影响很小，因此翻译起始的小分子抑制剂具有实现广泛治疗窗口的良好潜力。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，它是翻译起始级联反应中的关键角色，以努力确定有效和选择性的临床前候选对象。

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.