Discovery of a Covalent Kinase Inhibitor from a DNA-Encoded Small-Molecule Library × Protein Library Selection

• DOI: 10.1021/jacs.7b04880
• Publication Date: 2017-07-09T15:37:02Z
• Authors: Alix I. Chan; Lynn M. McGregor; Tara Jain; David R. Liu
• Keywords: Small Molecule Libraries; Structure-Activity Relationship; 0303 health sciences; 03 medical and health sciences; Molecular Structure; Peptide Library; Drug Discovery; Humans; DNA; MAP Kinase Kinase 6; Ligands; Protein Kinase Inhibitors

We previously reported interaction determination using unpurified proteins (IDUP), a method to selectively amplify DNA sequences encoding ligand:target pairs from a mixture of DNA-linked small molecules and unpurified protein targets in cell lysates. In this study, we applied IDUP to libraries of DNA-encoded bioactive compounds and DNA-tagged human kinases to identify ligand:protein binding partners out of 32 096 possible combinations in a single solution-phase library × library experiment. The results recapitulated known small molecule:protein interactions and also revealed that ethacrynic acid is a novel ligand and inhibitor of MAP2K6 kinase. Ethacrynic acid inhibits MAP2K6 in part through alkylation of a nonconserved cysteine residue. This work validates the ability of IDUP to discover ligands for proteins of biomedical relevance.