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Issue 7, 2016
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Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties

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Abstract

DNA-encoded chemical libraries are increasingly used to identify leads for drug discovery or chemical biology. Despite the resurging interest in covalent inhibitors, libraries are typically designed with synthon filtered out for reactive functionalities that can engage a target through covalent interactions. Herein, we report the synthesis of two libraries containing Michael acceptors to identify cysteine reactive ligands. We developed a simple procedure to discriminate between covalent and high affinity non-covalent inhibitors using DNA display of the library in a microarray format. The methodology was validated with known covalent and high affinity non-covalent kinase inhibitors. Screening of the library revealed novel covalent inhibitors for MEK2 and ERBB2.

Graphical abstract: Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties

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Publication details

The article was received on 30 Apr 2016, accepted on 21 Jun 2016 and first published on 22 Jun 2016


Article type: Research Article
DOI: 10.1039/C6MD00242K
Citation: Med. Chem. Commun., 2016,7, 1340-1351
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    Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties

    C. Zambaldo, J.-P. Daguer, J. Saarbach, S. Barluenga and N. Winssinger, Med. Chem. Commun., 2016, 7, 1340
    DOI: 10.1039/C6MD00242K

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