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8-Hydroxyquinoline derivatives suppress GLI1-mediated transcription through multiple mechanisms

Jiachen Wen1, Radha Charan Dash1, Angela M Zaino1

  • 1Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Unit 3092, Storrs, CT 06029-3092, United States.

Bioorganic Chemistry
|February 1, 2023
PubMed

Insights

Researchers developed a novel 8-hydroxyquinoline scaffold to inhibit GLI1, a key protein in cancer signaling pathways. Compound 39 shows enhanced GLI1 inhibition, suggesting potential for new cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Aberrant Hedgehog (Hh) signaling pathway activation is common in human cancers.
  • GLI1, the effector of the Hh pathway, also regulates Hh-independent cancer pathways.
  • Targeting GLI1 with small molecule inhibitors shows anti-cancer promise, but further development is needed.

Purpose of the Study:

  • To systematically investigate the structure-activity relationships of an 8-hydroxyquinoline scaffold for GLI1 inhibition.
  • To identify optimized GLI1 inhibitors with improved anti-cancer activity.
  • To explore potential roles of SRC family kinases in GLI1 transcriptional regulation.

Main Methods:

  • Structure-activity relationship (SAR) study of 8-hydroxyquinoline derivatives.
  • Biophysical assays to assess GLI1 inhibition.
  • Cellular experiments to evaluate compound efficacy and mechanism of action.

Main Results:

  • A series of novel GLI1 inhibitors based on the 8-hydroxyquinoline scaffold were synthesized and characterized.
  • Compound 39 emerged as a significantly enhanced GLI1 inhibitor with improved potency compared to the lead compound.
  • Evidence suggests SRC family kinases may play a role in regulating oncogenic GLI1 activity.

Conclusions:

  • The 8-hydroxyquinoline scaffold is a viable platform for developing potent GLI1 inhibitors.
  • Compound 39 represents a promising candidate for further preclinical development in cancers driven by GLI1.
  • Further research into the interplay between SRC family kinases and GLI1 may reveal new therapeutic strategies.
Keywords:
8-HydroxyquinolineGLI1 inhibitorHedgehog pathwaySrc kinaseStructure-based drug design

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