Salcius, Michael, Bauer, Andras, Hao, Qin, Li, Shu, Tutter, Antonin, Raphael, Jacob, Haggarty, Stephen, Tallarico, John, Michaud, Gregory and Jahnke, Wolfgang (2014) SEC-TID: A label-free method for small-molecule target identification. Journal of Biomolecular Screening, 19 (6). pp. 917-927. ISSN 1552-454X

Abstract

Bioactive small molecules are an invaluable source of therapeutics and chemical probes for exploring biological pathways. Yet, significant hurdles in drug discovery often come from lacking a comprehensive view of the target(s) for both early tool molecules and even late-stage drugs. To address this challenge, a method is provided that allows for assessing the interactions of small molecules with thousands of targets without any need to modify the small molecule of interest or attach any component to a surface. We describe size-exclusion chromatography for target identification (SEC-TID), a method for accurately and reproducibly detecting ligand-macromolecular interactions for small molecules targeting nucleic acid and several protein classes. We report the use of SEC-TID, with a library consisting of approximately 1000 purified proteins derived from the protein databank (PDB), to identify the efficacy targets tankyrase 1 and 2 for the Wnt inhibitor XAV939. In addition, we report novel interactions for the tumor-vascular disrupting agent vadimezan/ASA404 (interacting with farnesyl pyrophosphate synthase) and the diuretic mefruside (interacting with carbonic anhydrase XIII). We believe this method can dramatically enhance our understanding of the mechanism of action and potential liabilities for small molecules in drug discovery pipelines through comprehensive profiling of candidate druggable targets. © 2014 Society for Laboratory Automation and Screening.

Item Type:	Article
Keywords:	liquid chromatography-mass spectrometry nucleic acids proteins size-exclusion chromatography small molecules target identification
Date Deposited:	25 Nov 2017 00:45
Last Modified:	25 Jan 2019 00:46
URI:	https://oak.novartis.com/id/eprint/10268