A Specific and Covalent JNK-1 Ligand Selected from an Encoded Self-Assembling Chemical Library

作者：Zimmermann Gunther; Rieder Ulrike; Bajic Davor; Vanetti Sara; Chaikuad Apirat; Knapp Stefan; Scheuermann Jorg; Mattarella Martin^*; Neri Dario^*

来源：Chemistry - A European Journal, 2017, 23(34): 8152-8155.

DOI：10.1002/chem.201701644

• covalent inhibitors
• DNA-encoded chemical libraries
• drug discovery
• kinases
• targetable cysteine

We describe the construction of a DNA-encoded chemical library comprising 148 135 members, generated through the self-assembly of two sub-libraries, containing 265 and 559 members, respectively. The library was designed to contain building blocks potentially capable of forming covalent interactions with target proteins. Selections performed with JNK1, a kinase containing a conserved cysteine residue close to the ATP binding site, revealed the preferential enrichment of a 2-phenoxynicotinic acid moiety (building block A82) and a 4-(3,4-difluorophenyl)- 4-oxobut-2-enoic acid moiety (building block B272). When the two compounds were joined by a short PEG linker, the resulting bidentate binder (A82-L-B272) was able to covalently modify JNK1 in the presence of a large molar excess of glutathione (0.5 mm), used to simulate intracellular reducing conditions. By contrast, derivatives of the individual building blocks were not able to covalently modify JNK1 in the same experimental conditions. The A82-L-B272 ligand was selective over related kinases (BTK and GAK), which also contain targetable cysteine residues in the vicinity of the active site.

• 出版日期2017-6-16