Issue 22, 2018

Design and synthesis of (aza)indolyl maleimide-based covalent inhibitors of glycogen synthase kinase 3β

Abstract

As an important kinase in multiple signal transduction pathways, GSK-3β has been an attractive target for chemical probe discovery and drug development. Compared to numerous reversible inhibitors that have been developed, covalent inhibitors of GSK-3β are noticeably lacking. Here, we report the discovery of a series of covalent GSK-3β inhibitors by optimizing both non-covalent interactions and reactive groups. Among these covalent inhibitors, compound 38b with a mild α-fluoromethyl amide reactive group emerges as a selective and covalent inhibitor against GSK-3β, effectively inhibits the phosphorylation of glycogen synthase and tau protein, and increases β-catenin's levels in living cells. In addition, compound 38b is highly permeable and not a substrate of P-glycoprotein.

Graphical abstract: Design and synthesis of (aza)indolyl maleimide-based covalent inhibitors of glycogen synthase kinase 3β

Supplementary files

Article information

Article type
Paper
Submitted
15 Mar 2018
Accepted
01 May 2018
First published
21 May 2018

Org. Biomol. Chem., 2018,16, 4127-4140

Design and synthesis of (aza)indolyl maleimide-based covalent inhibitors of glycogen synthase kinase 3β

Z. Yang, H. Liu, B. Pan, F. He and Z. Pan, Org. Biomol. Chem., 2018, 16, 4127 DOI: 10.1039/C8OB00642C

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