Technologies to enable automated manufacturing of validated pharmaceutical hits

新药的开发是一项非常缓慢和昂贵的工作，其中包括一系列容易发生风险的步骤。制药业的最终目标是将药物开发的早期阶段转变为自动化生产过程。可以说，组合方法是实现这一目标的最有希望的手段。这种方法从产生一个包含10亿种不同化合物的组合库开始，然后逐步减少到筛选命中、验证命中、临床前线索、临床候选药物，最后是批准的药物。获得一种批准的药物需要数千次有效的点击--确认与治疗靶点结合的化合物。所需的大量验证命中需要它们的自动化制造。目前，验证的命中率是通过研究级流程的组合生成的，不能简化为制造流程。在这里，我们建议通过开发一种建立在稳健工艺基础上的颠覆性技术来解决这一瓶颈，该技术将促进经过验证的药物成功的自动化制造。该项目将由一个跨学科的学术团队(约克大学的Krylov和Hili的团队)与两家制药公司(Alphora Research和GSK Canada)和一家仪器开发公司(SCIEX)合作实施。这3家公司参与了可行性研究，结果发表了5份联合出版物，申请了2项专利，并公布了一项发明。该项目预计将产生：(1)几个相关研究领域的新知识；(2)具有高度可行性的实用技术；(3)实习生所需的行业技能。开发的技术将通过授权给支持组织和其他公司进行商业化，可能包括一家剥离出来的公司。受训人员将受雇于支持公司和其他技术许可方。由于新药的推出速度更快，使用拟议的制造技术不仅会带来经济效益，还会带来健康益处。

Development of new drugs is a very slow and expensive undertaking that includes a sequence of risk-prone steps. The ultimate goal of the pharmaceutical industry is to transform early stages of drug development into an automated manufacturing process. The combinatorial approach is arguably the most promising means of achieving this goal. This approach starts with production of a combinatorial library, containing a billion different compounds, and followed by its step-by-step reduction to screening hits, validated hits, pre-clinical leads, clinical candidates, and, eventually, an approved drug. Obtaining a single approved drug requires thousands of validated hits -- compounds with confirmed binding to a therapeutic target. The very large number of required validated hits necessitates their automated manufacturing. Currently, validated hits are generated via a combination of research-grade processes, which cannot be streamlined into a manufacturing flow. Here we propose to resolve this bottleneck via development of a disruptive technology built upon robust processes that will facilitate automated manufacturing of validated pharmaceutical hits. The project will be carried out by an interdisciplinary academic team (Krylov's and Hili's groups at York University) in collaboration with two pharmaceutical companies (Alphora Research and GSK Canada) and an instrumentation-development company (SCIEX). The 3 companies participated in the feasibility study, which led to 5 joint publications, 2 patent applications, and an invention disclosure. The project is expected to generate: (i) new knowledge in several related areas of research, (ii) a highly-enabling practical technology, and (iii) industry-demanded skills for the trainees. The developed technology will be commercialized via licensing to the supporting organizations and other companies, potentially including a spin off company. Trainees will be hired by the supporting companies and other technology licensors. The use of the proposed manufacturing technology will lead not only to economic benefits but also to health benefits due to the faster introduction of new drugs.