Related Experiment Video
Updated: May 17, 2025
07:03
Large Scale Zebrafish-Based In vivo Small Molecule Screen
Published on: December 30, 2010
13.4K
Evaluation of Benzo[cd]indol-2(1H)-ones as Downstream Hedgehog Pathway Inhibitors
Ioannis A Tsakoumagkos1, Quentin T L Pasquer1, Christian-Louis Guillod1
1Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland.
Chemistryopen
|April 14, 2025
Summary
Benzo[cd]indol-2(1H)-ones are novel downstream Hedgehog (HH) pathway inhibitors. This study shows their potential for epigenetic cancer therapy by reducing GLI levels and cancer cell viability.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Hedgehog (HH) signaling pathway dysregulation drives various cancers.
- Epigenetic targeting offers a promising therapeutic strategy for HH-driven malignancies.
Purpose of the Study:
- To identify and characterize novel downstream inhibitors of the Hedgehog signaling pathway.
- To evaluate the therapeutic potential of benzo[cd]indol-2(1H)-ones in HH pathway-driven cancers.
Main Methods:
- Screening of benzo[cd]indol-2(1H)-ones as HH pathway inhibitors.
- Assessment of compound potency in various HH pathway cell models.
- Analysis of cellular and ciliary GLI levels and BRD2 expression.
- Development of a competition assay to assess BET bromodomain binding.
- Evaluation of compound effects on cancer cell viability.
Main Results:
- Benzo[cd]indol-2(1H)-one 1 demonstrated sub-micromolar potency against HH pathway models.
- Compound 1 reduced cellular and ciliary GLI levels and increased BRD2 levels.
- Compound 1 competed with a known degrader for binding to BET bromodomains.
- Compound 1 reduced the viability of GLI-driven lung cancer cells and medulloblastoma spheroids.
Conclusions:
- The benzo[cd]indol-2(1H)-one scaffold represents a promising class of compounds for epigenetic targeting of the HH pathway.
- These inhibitors show potential for treating cancers driven by HH pathway activation.
