A Systems Chemical Biology Paradigm to Accelerate the Discovery of New Medicines for Patients: A Prosperity Partnership for a Healthier Nation

加速为患者发现新药的系统化学生物学范式：打造更健康国家的繁荣伙伴关系

• 批准号: EP/V038028/1
• 负责人: Simon Boulton
• 金额: $ 558.06万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FV038028%2F1
• 关键词: Systems; Chemical; Biology; Paradigm; Accelerate

Discovery and development of new medicines for patients is a long and complex process with an inherently low probability of success. Fortunately, rapid advances in technologies to read, interpret, and precisely manipulate the 'genetic code' are transforming our understanding of how small genetic variations can affect the onset of human disease.Subtle deviations in genetic sequence may lead to alteration in 'proteins' (basic building blocks of human cells) which, in turn, can influence the behaviour of specific cell types and eventually result in establishment of disease. Most medicines are therefore targeted towards a specific protein - normally to suppress, or enhance, the function of this protein. With many potential genes being associated with disease, the challenge of working through all these possible associations is daunting: there are a great many factors to evaluate. In most drug discovery campaigns, an early goal will be to identify chemical 'probes' (prototype drug molecules) that can precisely interfere with a given target to understand its therapeutic potential. Typically, this is a slow process which has several stages: firstly, producing small amounts of isolated protein; next, screening large 'libraries' of compounds (often more than 1,000,000); then following up the most promising compounds with experiments in human cells to study the target in question. This process can take many months tocomplete and must be repeated for each target of interest.The purpose of this Prosperity Partnership is to develop and industrialise emerging technology in Chemical Biology employing 'reactive fragment screening'. The exciting potential of this approach is its ability to simultaneously identify new, disease-relevant, protein targets and the chemical probes needed to study them in live cells. This has the advantage of bypassing the need for protein production and opens the possibility of studying many proteins in parallel rather than one at a time.'Fragments' are stripped down versions of drug molecules which are much less complex than their fully elaborated counterparts. Consequently, the number of fragments required to populate a library is much smaller than a traditional screening library (100-1,000 molecules versus 1,000,000 or more) which typically accelerates the process of screening compounds. Although fragments do not bind strongly to their protein targets, by introducing a reactive molecular 'feature' on to each library compound it is possible to permanently capture the full range of targets bound by each fragment.Subsequently, mass-spectrometry based 'chemoproteomics' (a sensitive analytical technique) can be used to build a map of the proteins which are captured by each fragment molecule in a disease-relevant cellular context. By adopting advanced computational techniques, it will be possible to link together outcomes of experiments involving 'genetic manipulation' with chemistry-directed experiments involving 'protein manipulation' to observe how each of these treatments changes the behaviour of a cell in a disease setting.Although more technically demanding, this advanced technology will enable protein targets to be advanced into full drug discovery at a faster pace and with higher levels of confidence than previously possible. Given the inherent difficulties of discovering and developing new medicines, and the high failure rates, new technologies which can reduce bottlenecks in discovery will enable more cost-effective development of new medicines and will ultimately benefit society as a whole.The Prosperity Partnership will dramatically expand the fruitful collaborative relationship between GSK and the Francis Crick Institute, established 5 years ago, which has already led to chemical probe-driven research breakthroughs. To achieve the goals of this ambitious Partnership, GSK and Crick scientists will work side-by-side at our Stevenage and London research centres.

为患者发现和开发新药是一个漫长而复杂的过程，成功的可能性本来就很低。幸运的是，读取、解释和精确操纵“遗传密码”的技术的快速进步正在改变我们对微小遗传变异如何影响人类疾病发病的理解。基因序列的细微偏差可能会导致“蛋白质”（人类细胞的基本组成部分）的改变，而“蛋白质”反过来又会影响特定细胞类型的行为，并最终导致疾病的发生。因此，大多数药物都针对特定蛋白质 - 通常是为了抑制或增强该蛋白质的功能。由于许多潜在基因与疾病相关，研究所有这些可能的关联的挑战是艰巨的：有很多因素需要评估。在大多数药物发现活动中，早期目标是识别能够精确干扰给定靶点以了解其治疗潜力的化学“探针”（原型药物分子）。通常，这是一个缓慢的过程，分为几个阶段：首先，产生少量的分离蛋白质；接下来，筛选大型化合物“库”（通常超过 1,000,000 个）；然后通过人体细胞实验追踪最有前途的化合物，以研究相关靶点。这一过程可能需要数月才能完成，并且必须针对每个感兴趣的目标重复进行。这一繁荣合作伙伴关系的目的是利用“反应片段筛选”开发化学生物学新兴技术并使其产业化。这种方法令人兴奋的潜力在于它能够同时识别新的、与疾病相关的蛋白质靶标以及在活细胞中研究它们所需的化学探针。这样做的优点是绕过了蛋白质生产的需要，并开启了并行研究多种蛋白质而不是一次研究一种蛋白质的可能性。“片段”是药物分子的精简版本，比完全精心设计的对应物复杂得多。因此，填充文库所需的片段数量比传统的筛选文库（100-1,000 个分子与 1,000,000 或更多）少得多，这通常会加速筛选化合物的过程。尽管片段不会与其蛋白质靶标牢固结合，但通过在每个库化合物上引入反应性分子“特征”，可以永久捕获每个片段所结合的全部靶标。随后，可以使用基于质谱的“化学蛋白质组学”（一种灵敏的分析技术）来构建每个片段分子在疾病相关细胞环境中捕获的蛋白质图谱。通过采用先进的计算技术，将有可能将涉及“基因操纵”的实验结果与涉及“蛋白质操纵”的化学指导实验联系起来，以观察每种治疗方法如何改变疾病环境中细胞的行为。尽管技术要求更高，但这种先进技术将使蛋白质靶点能够以比以前更快的速度和更高的置信度进入全面的药物发现。鉴于发现和开发新药的固有困难以及较高的失败率，能够减少发现瓶颈的新技术将使新药的开发更具成本效益，并最终造福整个社会。繁荣合作伙伴关系将极大地扩大葛兰素史克与弗朗西斯·克里克研究所之间富有成效的合作关系，该合作关系于 5 年前建立，已经带来了化学探针驱动的研究突破。为了实现这一雄心勃勃的合作目标，葛兰素史克和克里克科学家将在我们的斯蒂夫尼奇和伦敦研究中心并肩工作。

项目成果

A chemoproteomic platform for reactive fragment profiling against the deubiquitinases

用于针对去泛素酶进行反应片段分析的化学蛋白质组学平台

• DOI: 10.1101/2023.02.01.526632
• 发表时间: 2023
• 作者: Cookson R

Efficient Ligand Discovery Using Sulfur(VI) Fluoride Reactive Fragments

使用六氟化硫反应片段高效发现配体

• DOI: 10.26434/chemrxiv-2022-6mt7k-v2
• 发表时间: 2022
• 作者: Aatkar A

Efficient Ligand Discovery Using Sulfur(VI) Fluoride Reactive Fragments.

• DOI: 10.1021/acschembio.3c00034
• 发表时间: 2023-09-15
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Aatkar, Arron;Vuorinen, Aini;Longfield, Oliver E.;Gilbert, Katharine;Peltier-Heap, Rachel;Wagner, Craig D.;Zappacosta, Francesca;Rittinger, Katrin;Chung, Chun-wa;House, David;Tomkinson, Nicholas C. O.;Bush, Jacob T.
• 通讯作者: Bush, Jacob T.

Profiling Sulfur(VI) Fluorides as Reactive Functionalities for Chemical Biology Tools and Expansion of the Ligandable Proteome.

• DOI: 10.1021/acschembio.2c00633
• 发表时间: 2023-02-17
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Gilbert KE;Vuorinen A;Aatkar A;Pogány P;Pettinger J;Grant EK;Kirkpatrick JM;Rittinger K;House D;Burley GA;Bush JT
• 通讯作者: Bush JT

A chemoproteomic platform for selective deubiquitinase inhibitor discovery

• DOI: 10.1016/j.xcrp.2023.101636
• 发表时间: 2023-10-18
• 期刊: CELL REPORTS PHYSICAL SCIENCE
• 影响因子: 8.9
• 作者: Cookson，Rosa;Vuorinen，Aini;Bush，Jacob T.
• 通讯作者: Bush，Jacob T.