Rapid Discovery of a Novel Series of Abl Kinase Inhibitors by Application of an Integrated Microfluidic Synthesis and Screening Platform

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• 作者：Bimbisar Desai ; Karen Dixon ; Elizabeth Farrant ; Qixing Feng ; Karl R. Gibson ; Willem P. van Hoorn ; James Mills ; Trevor Morgan ; David M. Parry ; Manoj K. Ramjee ; Christopher N. Selway ; Gary J. Tarver ; Gavin Whitlock ; Adrian G. Wright
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：56
• 期：7
• 页码：3033-3047
• 全文大小：784K
• 年卷期：v.56,no.7(April 11, 2013)
• ISSN：1520-4804

文摘

Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure鈥揳ctivity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC₅₀ > 8 against Abl kinase 鈥?both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases.