Design of Macrocyclic Inhibitors of the NEMO/IKKa/b Protein-Protein Interaction

NEMO/IKKa/b 蛋白质-蛋白质相互作用大环抑制剂的设计

基本信息

批准号：
8306924
负责人：
Adrian Whitty
金额：
$ 46.17万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8306924
关键词：
Ablation Affinity Algorithms Attenuated Binding Biochemical Biochemistry Biological Biological Assay Biology Cells Characteristics Chemicals Chronic Complex Computer Simulation Development Disease Drug Delivery Systems Ensure Equilibrium Fluorescence Polarization Goals Human Human Pathology Hyperactive behavior Inflammation Inflammatory Knowledge Lead Learning Libraries Ligands Liver Microsomes Macrocyclic Compounds Malignant Neoplasms Measurable Measures Methodology Methods Monitor NF-kappa B Nature Pathway interactions Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phosphotransferases Property Proteins Public Health Reporting Signal Pathway Signal Transduction Site Solubility Source Structure System Testing Work X-Ray Crystallography aqueous base computational chemistry design drug development drug discovery experience improved inhibitor/antagonist novel novel strategies protein protein interaction public health relevance scaffold small molecule stereochemistry virtual

项目摘要

DESCRIPTION (provided by applicant): The overall project goal is to develop new approaches for discovering "drug-like" small molecule inhibitors against challenging protein-protein interaction (PPI) interfaces. It tests the hypothesis that appropriately designed synthetic macrocycles can inhibit PPI targets while maintaining good drug-like properties. The test system is the intracellular PPI target NF-?B essential modulator (NEMO), a component of the inhibitor of ?B kinase (IKK) complex. Chronic hyperactivity of the NF-?B pathway is found in human inflammatory diseases and cancers. Inhibiting the interaction of NEMO with IKK, as a more targeted alternative to completely ablating all IKK kinase activity, represents a promising new approach for attenuating inflammation. The three Specific Aims are: 1. Perform a virtual fragment screen of the IKK binding domain of NEMO. A novel algorithm (FTMAP) will be used against the PPI target sites. The results will inform the design of novel synthetic acyclic and macrocyclic libraries for synthesis and testing as NEMO inhibitors. 2. Synthesize macrocycles and acyclic inhibitors (from Aim 1), and test them for inhibition of NEMO/IKK binding in a fluorescence polarization assay. Hits will be characterized biochemically and structurally and further optimized through medicinal chemistry. All the compounds will be assessed in assays that measure ADME properties (e.g., solubility, cell permeability and liver microsome stability). The consequences of different macrocyclic designs for these key pharmaceutical properties will thus be determined independently of their activity against NEMO. 3. Characterize promising hits and leads (from Aim 2) using biochemical, biophysical, structural and biological approaches, to elucidate the nature of their interactions with NEMO, determine the origins of the binding energy they generate with the target, and assess their utility as biological probes and/or drug leads. The project team encompasses strong expertise and highly relevant experience across every aspect of the project, including computational chemistry, macrocycle synthesis, X-ray crystallography, drug discovery, and NF-?B pathway biology. The project will provide theoretical and methodological advances in drug discovery against PPI targets. It will elucidate the physicochemical and structural origins and hallmarks of druggability at a PPI interface, and will establish the utility of novel in silico fragment-based approaches and synthetic macrocycles as sources for drug-like inhibitors against such targets. PUBLIC HEALTH RELEVANCE: The goal of this project is to target a particularly challenging class of drug targets, - protein-protein interactions - with small molecule (i.e., synthetic organic) drugs. It aims to inhibit NF-?B Essential Modulator (NEMO), a component of the NF-?B signaling pathway, which is misregulated in human pathologies such as inflammatory disease and cancer. Inhibiting this pathway represents a promising new approach for the development of effective drugs and, consequently, is highly relevant to public health.

描述（由申请人提供）：总体项目目标是开发新方法来发现针对具有挑战性的蛋白质-蛋白质相互作用（PPI）界面的“类药物”小分子抑制剂。它测试了这样的假设：适当设计的合成大环化合物可以抑制 PPI 靶标，同时保持良好的药物特性。测试系统是细胞内 PPI 靶标 NF-κB 必需调节剂 (NEMO)，它是 κB 激酶 (IKK) 复合物抑制剂的一个组成部分。 NF-κB 通路的慢性过度活跃存在于人类炎症性疾病和癌症中。抑制 NEMO 与 IKK 的相互作用，作为完全消除所有 IKK 激酶活性的更有针对性的替代方案，代表了一种有前途的减轻炎症的新方法。三个具体目标是： 1. 对 NEMO 的 IKK 结合域进行虚拟片段筛选。将针对 PPI 目标站点使用一种新颖的算法 (FTMAP)。结果将为新型合成无环和大环库的设计提供信息，用于 NEMO 抑制剂的合成和测试。 2. 合成大环化合物和无环抑制剂（来自目标 1），并在荧光偏振测定中测试它们对 NEMO/IKK 结合的抑制作用。将对命中的生物化学和结构进行表征，并通过药物化学进一步优化。所有化合物都将在测量 ADME 特性（例如溶解度、细胞通透性和肝微粒体稳定性）的测定中进行评估。因此，不同大环设计对这些关键药物特性的影响将独立于它们针对 NEMO 的活性而确定。 3. 使用生物化学、生物物理、结构和生物学方法表征有前景的命中和先导化合物（来自目标 2），以阐明它们与 NEMO 相互作用的性质，确定它们与目标产生的结合能的来源，并评估它们的效用：生物探针和/或药物引线。项目团队在项目的各个方面都拥有强大的专业知识和高度相关的经验，包括计算化学、大环合成、X 射线晶体学、药物发现和 NF-κB 通路生物学。该项目将为针对 PPI 靶点的药物发现提供理论和方法上的进展。它将阐明 PPI 界面的物理化学和结构起源以及成药性特征，并将建立基于计算机片段的新型方法和合成大环化合物作为针对此类靶标的药物抑制剂来源的效用。公共健康相关性：该项目的目标是针对一类特别具有挑战性的药物靶标，即蛋白质与蛋白质相互作用，以及小分子（即合成有机）药物。它的目的是抑制 NF-κB 必需调节剂 (NEMO)，这是 NF-κB 信号通路的一个组成部分，该通路在炎症性疾病和癌症等人类病理学中受到错误调节。抑制这一途径代表了开发有效药物的一种有前途的新方法，因此与公共卫生高度相关。