title: Rapid discovery of a novel series of Abl kinase inhibitors by application of an integrated microfluidic synthesis and screening platform.
abstract: 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-activity 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--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.
authors: Cyclofluidic Ltd, Biopark, Broadwater Road, Welwyn Garden City AL7 3AX, UK.
authors: Bimbisar
authors: B
authors: Desai
authors: Karen
authors: K
authors: Dixon
authors: Elizabeth
authors: E
authors: Farrant
authors: Qixing
authors: Q
authors: Feng
authors: Karl R
authors: KR
authors: Gibson
authors: Willem P
authors: WP
authors: van Hoorn
authors: James
authors: J
authors: Mills
authors: Trevor
authors: T
authors: Morgan
authors: David M
authors: DM
authors: Parry
authors: Manoj K
authors: MK
authors: Ramjee
authors: Christopher N
authors: CN
authors: Selway
authors: Gary J
authors: GJ
authors: Tarver
authors: Gavin
authors: G
authors: Whitlock
authors: Adrian G
authors: AG
authors: Wright
mesh_terms: D000465:Algorithms; D055808:Drug Discovery; D044085:Microfluidics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases