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作的理解。基因序列的细微偏差可能导致“蛋白质”（人类细胞的基本组成部分）发生变化，进而影响特定细胞类型的行为，最终导致疾病的发生。因此，大多数药物都针对特定的蛋白质-通常是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有关，因此通过所有这些可能的关联进行工作的挑战是艰巨的：有很多因素需要评估。在大多数药物发现活动中，早期的目标将是确定可以精确干扰给定靶标的化学“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，有几个阶段：首先，生产少量分离的蛋白质;其次，筛选大型化合物“库”（通常超过1，000，000）;然后在人体细胞中进行实验，研究最有希望的化合物。这一过程可能需要数月才能完成，并且必须对每个感兴趣的目标重复进行。这个繁荣伙伴关系的目的是开发和工业化化学生物学中采用“反应片段筛选”的新兴技术。这种方法令人兴奋的潜力在于它能够同时识别新的疾病相关蛋白质靶标和在活细胞中研究它们所需的化学探针。这具有绕过蛋白质生产的需要的优点，并打开了并行研究许多蛋白质而不是一次一个的可能性。“片段”是药物分子的剥离版本，其复杂性远远低于其完全精心设计的对应物。因此，填充文库所需的片段数量远小于传统筛选文库（100- 1，000个分子对1，000，000个或更多），这通常加速了筛选化合物的过程。尽管片段不能与它们的蛋白质靶点强烈结合，但是通过在每个文库化合物上引入反应性分子“特征”，可以永久捕获由每个片段结合的全部靶点。随后，基于质谱的“化学蛋白质组学”（一种灵敏的分析技术）可以用于构建在疾病相关的细胞环境中由每个片段分子捕获的蛋白质的图谱。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”的化学导向实验联系起来，以观察这些治疗方法如何改变疾病环境中细胞的行为。这种先进的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。鉴于新药研发的固有困难和高失败率，能够减少研发瓶颈的新技术将使新药开发更具成本效益，并最终造福于整个社会。繁荣伙伴关系将极大地扩展GSK与弗朗西斯克里克研究所5年前建立的富有成效的合作关系，这已经导致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伙伴关系的目标，GSK和克里克的科学家将在我们的斯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.