A Novel Chemical Proteomics Platform to Expand Druggable Space

扩大药物空间的新型化学蛋白质组学平台

• 批准号: 9883136
• 负责人: Ping Cao
• 金额: $ 16.83万
• 依托单位: BRIDGENE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2019-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883136
• 关键词: Novel; Chemical; Proteomics; Platform; Expand

Abstract A bottleneck in drug discovery is the lack of high-quality small-molecule probes to validate the disease relevance of genes, particularly those with promising disease linkage but are considered “undruggable”, such as transcription factors and scaffolding proteins. Recently, covalent drugs have become a promising option to address a number of challenges such as low efficiency of lead discovery, resistance to targeted therapies, and poor druggability of many targets. We hypothesize that the druggable targets can be dramatically expanded by leveraging covalent chemistry in drug development. The TarGead Sciences team proposes to combine bio-orthogonal reactions with MS- based proteomics technology to create a novel platform that allows for the detection and quantification of the interactions between an electrophilic compound and thousands of proteins across the proteome. Specifically, we will synthesize a library of electrophilic probes based on privileged scaffolds as baits to fish out novel targets in various cell types (Aim 1).  A new chemical proteomic approach will be established to map and quantify the proteome-wide interactions of electrophilic probes in different cell lines (Aim 2). In Aim 3, we will optimize electrophilic leads for potent and selective functional modulation of select targets such as vacuolar ATPase. Our work will yield high-quality covalent leads for novel targets including the undruggable ones, paving the way for subsequent preclinical studies.

摘要 药物发现的一个瓶颈是缺乏高质量的小分子探针来验证 基因的疾病相关性，特别是那些有希望的疾病连锁，但被认为是 例如，转录因子和支架蛋白。最近，共价药物 成为一个有前途的选择，以解决一些挑战，如低效率的铅 发现，对靶向治疗的抗性，以及许多靶点的可药用性差。我们假设 通过利用药物中的共价化学， 发展Targead Sciences团队提出将联合收割机生物正交反应与MS- 基于蛋白质组学技术，创建一个新的平台，允许检测和 亲电化合物与数千种蛋白质之间相互作用的定量 在蛋白质组中。具体来说，我们将合成亲电探针库， 作为诱饵的特权支架在各种细胞类型中钓出新的靶点（目标1）。 将建立蛋白质组学方法来绘制和量化蛋白质组范围内的相互作用， 不同细胞系中的亲电探针（Aim 2）。在目标3中，我们将优化亲电引线， 有效和选择性的功能调节选择的目标，如液泡ATP酶。我们的工作将 为新靶点（包括非药物靶点）产生高质量的共价先导物，为 随后的临床前研究。