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

为患者发现和开发新药是一个漫长而复杂的过程，成功的可能性天生就很低。幸运的是，在读取、解释和精确操纵“遗传密码”的技术上的快速进步正在改变我们对微小基因变异如何影响人类疾病发病的理解。基因序列中的微小偏差可能会导致“蛋白质”(人类细胞的基本构件)发生变化，进而影响特定细胞类型的行为，并最终导致疾病的发生。因此，大多数药物都针对一种特定的蛋白质--通常是为了抑制或增强这种蛋白质的功能。由于许多潜在的基因与疾病相关，研究所有这些可能的关联是一项艰巨的挑战：需要评估的因素很多。在大多数药物发现活动中，早期目标将是识别能够精确干扰给定靶点的化学“探针”(原型药物分子)，以了解其治疗潜力。通常，这是一个缓慢的过程，分为几个阶段：首先，生产少量的分离蛋白；然后，筛选大量的化合物(通常超过100万)；然后在人体细胞中进行实验，研究目标最有希望的化合物。这一过程可能需要几个月的时间才能完成，每个感兴趣的目标都必须重复这一过程。这一繁荣伙伴关系的目的是开发化学生物学中的新兴技术，并将其产业化，这些技术使用的是“活性片段筛选”。这种方法的令人兴奋的潜力是它能够同时识别新的、与疾病相关的蛋白质靶点和在活细胞中研究它们所需的化学探针。这样做的好处是绕过了蛋白质生产的需要，并开启了同时研究多个蛋白质的可能性，而不是一次研究一个蛋白质。“碎片”是被剥离出来的药物分子的版本，它们比完全精心制作的分子要简单得多。因此，填充文库所需的片段数量比传统的筛选文库(100-1,000个分子比1,000,000个或更多)要少得多，后者通常会加快化合物的筛选过程。尽管片段不会强烈地结合到它们的蛋白质靶标上，但通过给每个文库化合物引入一个反应性的分子‘特征’，就有可能永久捕获每个片段结合的所有靶点。因此，基于质谱学的‘化学蛋白质组学’(一种灵敏的分析技术)可以用来建立每个片段分子在与疾病相关的细胞环境中捕获的蛋白质的图谱。通过采用先进的计算技术，可以将涉及“基因操作”的实验结果与涉及“蛋白质操作”的化学指导实验的结果联系起来，以观察每一种治疗方法如何改变细胞在疾病环境中的行为。尽管技术要求更高，但这项先进技术将使蛋白质靶标能够以比以前更快的速度和更高的信心进入全面的药物发现。鉴于发现和开发新药的内在困难和高失败率，可以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，已导致化学探针驱动的研究突破。为了实现这一雄心勃勃的合作伙伴关系的目标，葛兰素史克和克里克的科学家将在我们的史蒂夫尼奇和伦敦研究中心并肩工作。

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.