Jump to main content
Jump to site search

Issue 22, 2018
Previous Article Next Article

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

Author affiliations

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

Back to tab navigation

Supplementary files

Publication details

The article was received on 15 Mar 2018, accepted on 01 May 2018 and first published on 21 May 2018


Article type: Paper
DOI: 10.1039/C8OB00642C
Citation: Org. Biomol. Chem., 2018,16, 4127-4140
  •   Request permissions

    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

Search articles by author

Spotlight

Advertisements