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

被引：68

作者：

Chang, Alix I.

McGregor, Lynn M. ^{[2
]}

Jain, Tara ^{[3
]}

Liu, David R. ^{[1
]}

机构：

[1] Harvard Univ, Broad Inst Harvard & MIT, Howard Hughes Med Inst, 75 Ames St, Cambridge, MA 02142 USA

[2] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA

[3] Harvard Med Sch, Boston, MA 02115 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2017年 / 139卷 / 30期

关键词：

IDENTIFICATION; TARGETS; DISPLAY; PAIRS;

D O I：

10.1021/jacs.7b04880

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 arid DNA-tagged human kinases to identify ligand:protein binding partners out of 32 096 possible combinations in a single solution-phase library X 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:

引用

页码：10192 / 10195

页数：4

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