Indirubin-3′-alkoxime derivatives for upregulation of Wnt signaling through dual inhibition of GSK-3β and the CXXC5-Dvl interaction

Doona Song, Yunja Lee, Min Jeong Kang, Jae Won Kim, Soung Hoon Lee, Kang Yell Choi, Eun Yeong Kim, Kiho Lee, Gyoonhee Han

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Glycogen synthase kinase-3β (GSK-3β) appears to be ordinarily expressed, and functionally redundant in Wnt/β-catenin signaling. The Wnt proteins induce transduction of a cytoplasmic protein, Dishevelled (Dvl) which negatively modulates GSK-3β activity. CXXC5 is a negative modulator of the Wnt/β-catenin signaling through the interaction with Dvl in the cytosol. This indicates that Wnt/β-catenin signaling could be efficiently modulated by controlling GSK-3β and the CXXC5-Dvl interaction. In this study, we designed a series of indirubin-3′-oxime and indirubin-3′-alkoxime derivatives containing various functional groups at the 5- or 6-position (R1) alongside alkyl or benzylic moieties at the 3′-oxime position (R2). These activate Wnt signaling through inhibitions of both GSK-3β and the CXXC5-Dvl protein–protein interaction, in addition, the improvement of pharmacological properties. The potent activity profiles of the synthesized compounds suggested that dual inhibition of GSK-3β and the CXXC5-Dvl interaction could be an appropriate approach towards safely and efficiently activating Wnt signaling. Thus, dual-targeting inhibitors are potentially better candidates for efficient activation of Wnt signaling compared to GSK-3β inhibitors.

Original languageEnglish
Article number105664
JournalBioorganic Chemistry
Volume121
DOIs
Publication statusPublished - 2022 Apr

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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