Macrocyclic Peptidyl Inhibitors of NEMO-IKK Interaction

NEMO-IKK 相互作用的大环肽基抑制剂

基本信息

批准号：
10653996
负责人：
Dehua Pei
金额：
$ 41.29万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10653996
关键词：
Affect Amino Acids Anti-Inflammatory Agents Autoimmune Diseases B-Lymphocytes Binding Biochemical Biological Assay Biological Response Modifiers Cancer Etiology Cancer Relapse Cancer cell line Cell Culture Techniques Cell physiology Cells Cellular Assay Cessation of life Characteristics Chemicals Chemoresistance Cisplatin Disease Dose Drug Kinetics Ensure Epithelial Cells Epithelial ovarian cancer Family Flow Cytometry Goals Grant Immune response In Vitro Inflammatory Libraries Luc Gene Maintenance Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mammalian Cell Metabolic Methods Modeling Mus Ovarian Pathway interactions Peptides Periodicity Permeability Pharmaceutical Preparations Phosphorylation Phosphotransferases Positioning Attribute Proliferating Property Proteins Recurrence Recurrent tumor Relapse Serum Signal Pathway Signal Transduction Solubility Stimulus Structure Surface T-Lymphocyte TNF gene Testing Therapeutic Agents Transcriptional Regulation Translating Treatment Efficacy Tumorigenicity United States Woman X-Ray Crystallography Xenograft Model analog anti-cancer aqueous cancer cell cancer stem cell cancer survival cell type human disease improved in silico in vivo inhibitor meter mortality novel ovarian neoplasm prevent programs protein protein interaction self-renewal small molecule inhibitor stem cell population stem cells stemness transcription factor tumor tumor progression

项目摘要

Project Summary NF-κB is a family of transcription factors that are expressed in all mammalian cell types and act as the master regulator of the immune response. Aberrant activation of NF-κB has been implicated in many inflammatory and autoimmune diseases, as well as cancer. NF-κB can be activated by two different signaling pathways, the canonical (or classical) pathway and the non-canonical pathway. Canonical NF-κB signaling involves a key interaction between inhibitor of κB (IκB)-kinase α/β (IKKα/β) and NEMO (also called IKKγ). Inhibition of the NEMO-IKKα/β interaction thus represents an attractive anti-inflammatory and anticancer strategy, as the inhibitor would block the NF-κB activity induced by pro-inflammatory stimuli but not the basal NF-κB activity, which is required for normal B- and T-cell function. Unfortunately, previous attempts to develop small-molecule inhibitors against this intracellular protein-protein interaction have been largely unsuccessful. In this project, we will explore cell-permeable macrocyclic peptides for inhibition of the NEMO-IKKα/β interaction. Specific Aim 1 is to further optimize the potency, selectivity, and other drug properties of a bicyclic peptidyl inhibitor (NI174-5; IC50 = 1.0 µM) discovered during our preliminary studies and biochemically, biologically, and structurally (by X-ray crystallography and in silico modeling) characterize the improved NEMO inhibitor(s). Specific Aim 2 is to determine the effect of NI174-5 (or an improved NEMO inhibitor) on ovarian cancer stem cells (CSC) in vitro and in vivo, as well as its ability to prevent tumor relapse following initial cisplatin treatment in an orthotopic ovarian tumor xenograft model.

项目概要 NF-κB 是一个转录因子家族，在所有哺乳动物细胞类型中表达，并充当 NF-κB 的异常激活与免疫反应的主要调节因子有关。许多炎症和自身免疫性疾病以及癌症都可以通过两种途径激活。不同的信号传导途径，典型（或经典）途径和非典型途径。典型的 NF-κB 信号传导涉及 κB (IκB)-激酶 α/β 抑制剂之间的关键相互作用 (IKKα/β) 和 NEMO（也称为 IKKγ）因此抑制 NEMO-IKKα/β 相互作用。有吸引力的抗炎和抗癌策略，因为抑制剂会阻断 NF-κB 活性由促炎刺激诱导，但不是由正常 B- 所需的基础 NF-κB 活性诱导不幸的是，之前曾尝试开发针对此的小分子抑制剂。在这个项目中，我们将探索细胞内蛋白质-蛋白质相互作用。用于抑制 NEMO-IKKα/β 相互作用的细胞渗透性大环肽的具体目标 1 是。进一步优化双环肽基抑制剂的效力、选择性和其他药物特性（NI174-5；IC50 = 1.0 µM）在我们的初步研究和生化、生物学方面发现，并在结构上（通过 X 射线晶体学和计算机建模）表征改进的 NEMO 具体目标 2 是确定 NI174-5（或改进的 NEMO 抑制剂）对药物的影响。卵巢癌干细胞（CSC）的体外和体内及其预防肿瘤复发的能力在原位卵巢肿瘤异种移植模型中进行初始顺铂治疗后。