Targeting central regulation of oncogenic signaling through inhibition of translation initiation complex eIF4F

癌症是一组广泛存在的疾病，对人类健康和社会产生有害影响。 经济负担。此外，对一线治疗的化疗耐药性的产生是导致 大多数死亡(超过90%)是肿瘤患者。蛋白质合成增加是一种关键特征，它与 在许多类型的人类癌症中具有发生、预后差和耐药的特点。真核启动因子 4F(EIF4F)，一个帽依赖的mRNA翻译起始复合体，形成一个中心节点，用于频繁上调 致癌途径有Myc、RAS、PI3K-AKT-mTOR等。对装配的基本要求和 EIF4F平移机械的运行是eIF4E和eIF4G亚单位之间的相互作用。抑制 这种蛋白质-蛋白质相互作用(PPI)最近被证明是一种可行的靶向翻译方法 入会仪式。然而，已发表的PPI抑制剂存在亲和力和溶解度低以及靶标外的问题。 效果。因此，我们的目标是开发新型的类药物和选择性的eIF4E/eIF4G小分子抑制剂 互动。我们的假设是，eIF4E表面的正则基序结合位点可以通过 模仿eIF4G。我们的计算方法确定了可能抑制这一现象的新型支架 通过靶向eIF4E表面的热点残基进行相互作用。这些化合物没有痛苦。 在eIF4E表面上扫描3D空间的特性和便利性。为了检验我们的假设，我们将继续 三个具体目标。目标1将专注于设计和合成具有类药物特性的新型PPI抑制剂。 这些合成的化合物将在荧光偏振和下拉分析中进行评估，以确定 AIM 2中的eIF4E/eIF4G相互作用抑制谱。AIM 3将通过测试高- 双荧光素酶分析中的亲和化合物。该方法可用于测定对CaP-2的抑制作用。 依赖与大小写无关的翻译。此外，选定的化合物将被测试其抗 对人类癌细胞系的增殖作用。

Cancer is a widespread group of diseases with deleterious effects on society with regard to human health and financial burden. Furthermore, the development of chemoresistance to first-line therapies is responsible for the majority of deaths (over 90%) in tumor patients. Elevated protein synthesis is a critical trait that is associated with genesis, poor prognosis, and drug resistance in many types of human cancers. Eukaryotic initiation factor 4F (eIF4F), a cap-dependent mRNA translation initiation complex forms a central node for frequently upregulated oncogenic pathways such as Myc, Ras, and PI3K-AKT-mTOR. An essential requirement for the assembly and operation of the eIF4F translational machinery is the interaction between subunits eIF4E and eIF4G. Inhibition of this protein-protein interaction (PPI) has been recently demonstrated as a viable approach to target translation initiation. However, the published PPI inhibitors suffer from low affinity and solubility issues along with off-target effects. Thus, our goal is to develop novel drug-like and selective small molecule inhibitors of eIF4E/eIF4G interaction. Our hypothesis is that the canonical motif-binding site on the surface of eIF4E can be targeted via mimicry of eIF4G. Our computational approach identified novel scaffolds that could potentially inhibit this interaction by targeting the hot-spot residues on the surface of eIF4E. These compounds are devoid of PAINS characteristics and facilitate scanning of 3D space on the eIF4E surface. To test our hypothesis, we will pursue three specific aims. Aim 1 will focus on the design and synthesis of novel PPI inhibitors with drug-like properties. These synthesized compounds will be assessed in fluorescence polarization and pull-down assays to determine the eIF4E/eIF4G interaction inhibition profile in Aim 2. Aim 3 will evaluate the cellular effects by testing the high- affinity compounds in a dual luciferase assay. This assay enables the determination of inhibition of cap- dependent versus cap-independent translation. Further, the selected compounds will be tested for their anti- proliferative effects on human cancer cell lines.