Small molecule direct binding by use of ASMS for target tractability assessment and high throughput hit identification

Recorded On: 02/05/2018

Affinity Selection Mass Spectrometry (ASMS), a label free assay that connects a binding event to the accurate mass identity of the ligand involved, is an established HTS triage platform at GSK that has been used to generate hit qualification data on more than 60 targets during the past three years. As part of a paradigm shift to screen novel targets, we are exploring the use of ASMS for hit identification, target tractability assessments and tool compound identification.  The benefits include reduced cycle time through streamlined assay development, and reduced attrition through identification of compounds that directly engage the target protein. A mass-encoded 180,000 compound library has been created for ASMS screening, and is comprised of compounds that represent aspirational chemical space in terms of molecular weight, cLogP and property forecast index. The output of the ASMS platform has been evaluated against existing target-specific biochemical and biophysical data to develop a better methodology that maximizes the identification of biochemically active compounds while minimizing the overall hit rate. Nearly 85% of compounds with known biochemical and/or biophysical activity showed binding to a protein target with our platform. A sub-set of the full library is being used to evaluate target tractability, and has been used to screen 30+ historical targets, with the goal of correlating compound binding to tractability predictions.  Overall, ASMS tractability outcomes align well with Encoded Library Technology (ELT) and HTS tractability observations. From a methods optimization perspective, continued development of the sample preparation protocols and the LC-MS platform are being targeted to maximize sensitivity and increase platform throughput. Furthermore, the development of an end-to-end informatics solution will complement the analytical platform. This presentation will highlight the ASMS platform developed for hit identification and target tractability assessments and illustrate its application of a kinase screening campaign as a proof of concept.

Geoff Quinque


I have been in my current group for six years at GlaxoSmithKline within the Screening, Profiling & Mechanistic Biology Department. Our group is responsible for assay development, high throughput screening and compound profiling and mechanistic characterization of small molecules from target validation through pre-clinical candidate selection. 

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