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

通过抑制翻译起始复合物 eIF4F 靶向致癌信号传导的中枢调节

基本信息

批准号：
10714802
负责人：
Bhargav Ashokbhai Patel
金额：
$ 18.06万
依托单位：
SOUTHERN ILLINOIS UNIV AT EDWARDSVILLE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-07-01
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714802
关键词：
3-Dimensional A549 Address Affinity American Cancer Society Binding Binding Proteins Binding Sites Biological Assay Cancer cell line Cell Line Cell Proliferation Cessation of life Characteristics Chemoresistance Chronic Clinical Trials Complex Development Disease Docking Drug Kinetics Drug resistance Eukaryotic Initiation Factor-4F Evaluation FRAP1 gene Financial Hardship Fireflies Fluorescence Polarization Funding Goals Health Human In Vitro Interruption Luciferases MDA MB 231 Malignant Neoplasms Medicine Messenger RNA Neoplasm Metastasis Oncogenic Outcome Study PIK3CG gene Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phosphotransferases Play Principal Investigator Process Prognosis Property Protein Biosynthesis Protein Inhibition Proteins Proto-Oncogene Proteins c-akt Publishing Reaction Regulation Renilla Research Research Design Resistance Resistance development Ribosomes Role Scaffolding Protein Scanning Signal Pathway Signal Transduction Societies Solubility Structure Students Surface Testing Training Translation Initiation Translational Repression Translations United States Writing anti-cancer cancer cell cancer drug resistance cancer therapy career cell growth design helicase high throughput screening inhibitor mRNA Translation mimicry novel novel therapeutics operation pharmacophore programs protein protein interaction scaffold screening small molecule small molecule inhibitor targeted agent trait tumor tumor progression tumorigenesis

项目摘要

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.

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