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Activity-directed discovery of chemical probes of protein kinase biology

蛋白激酶生物学化学探针的活性导向发现

基本信息

批准号：
1939281
负责人：
金额：
--
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1939281
关键词：
Activity directed discovery chemical probes

项目摘要

Background: The availability of high quality probes can address the highly unsystematic historic exploration of the biology of proteins. This project will focus on ATP-competitive inhibitors of a protein kinase that would enable interrogation of its role protein kinase in key biology mechanisms.In preliminary work, fragments that bind the protein kinase have been identified. However, structure-based inhibitor discovery has been hampered by the inability to crystallise the kinase in complex with fragments. The project will therefore exploit activity-directed synthesis (ADS), Nelson's discovery approach that can enable productive fragment elaboration in the absence of structural information. The resulting probes will reveal insights into the cellular function of the protein kinase e.g. in conjunction with cell biology collaborators.Objectives:1. To identify an expanded range of binding fragments;2. To exploit ADS in the discovery of potent and selective ATP-competitive kinase inhibitors;3. To determine the structural basis of small molecule inhibition;4. To exploit the small molecule inhibitors as chemical probes of biological mechanisms.Novelty and timeliness:The discovery of potent and selective inhibitors of some protein kinases is challenging due to specific active site features; and a lack of structural information. ADS is a capability that is unique worldwide, and can support ligand discovery in the absence of structural information. Here, ADS will be exploited to discover the first potent and selective modulators of a specific protein kinase. Experimental approach:1. Biophysical techniques to discover and characterize binding fragments;2. Activity-directed synthesis to support fragment-based probe discovery;3. Protein crystallography to reveal the structural basis of inhibition;4. Preliminary cellular biology studies enabled by the novel probes.

背景：高质量探针的可获得性可以解决蛋白质生物学高度不系统的历史性探索。这个项目将集中在一种蛋白激酶的ATP竞争性抑制物上，这将使人们能够询问蛋白激酶在关键生物学机制中的作用。在初步工作中，已经鉴定出与蛋白激酶结合的片段。然而，基于结构的抑制剂的发现由于不能使带有片段的复杂的激酶结晶而受到阻碍。因此，该项目将利用活动定向合成(ADS)，这是纳尔逊的发现方法，可以在缺乏结构信息的情况下实现富有成效的片段精加工。由此产生的探针将揭示蛋白激酶的细胞功能，例如与细胞生物学合作者合作。目标：1.鉴定更大范围的结合片段；2.利用ADS发现有效和选择性的ATP竞争性激酶抑制剂；3.确定小分子抑制的结构基础；4.将小分子抑制剂用作生物机制的化学探针。新颖性和及时性：由于特定的活性部位特征，发现一些蛋白激酶的有效和选择性抑制剂是具有挑战性的；以及缺乏结构信息。ADS是一种在世界范围内独一无二的能力，可以在缺乏结构信息的情况下支持配体发现。在这里，ADS将被用来发现第一个有效的和选择性的特定蛋白激酶的调节器。实验方法：1.发现和表征结合片段的生物物理技术；2.活性导向合成，以支持基于片段的探针发现；3.蛋白质结晶学，以揭示抑制的结构基础；4.由新型探针实现的初步细胞生物学研究。