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Updated: Aug 14, 2025
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Visible-Light-Controlled Histone Deacetylase Inhibitors for Targeted Cancer Therapy
Laia Josa-Culleré1, Amadeu Llebaria1
1MCS, Laboratory of Medicinal Chemistry & Synthesis, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, 08034Barcelona, Spain.
Abstract:
The lack of selectivity of anticancer drugs limits current chemotherapy. Light-activatable drugs, whose activity can be precisely controlled with external light, could provide a more localized action of the drugs in the tumor, thus decreasing side effects and increasing efficacy. Herein, we introduce a series of photoswitchable azobenzene histone deacetylase inhibitors (HDACis) whose activity can be controlled by external visible light. Initial HDACis isomerized under ultraviolet light and were up to >50-fold more active under illumination than in the dark in enzyme assays. These were then optimized toward compounds responding to more permeable and less harmful green light by introducing o-halogen atoms into the azobenzene. Selected compounds decreased cell viability only under illumination in four different cancer cell lines. Overall, we present photoswitchable HDACis with optimized activation wavelengths, which inhibit enzyme activity and cell viability only upon illumination with visible light, contributing to the still limited toolbox of photoswitchable anticancer drugs.
Insights
Researchers developed new light-activatable anticancer drugs called photoswitchable histone deacetylase inhibitors (HDACis). These drugs show enhanced activity only when exposed to visible light, offering a more targeted chemotherapy approach.
Area of Science:
- Medicinal Chemistry
- Organic Chemistry
- Cancer Biology
Background:
- Current chemotherapy faces limitations due to poor selectivity of anticancer drugs.
- Light-activatable drugs offer potential for localized drug action, reducing side effects and improving efficacy.
- Histone deacetylase inhibitors (HDACis) are a class of anticancer agents with therapeutic potential.
Purpose of the Study:
- To design and synthesize novel photoswitchable azobenzene-based histone deacetylase inhibitors (HDACis).
- To control the activity of HDACis using external visible light for targeted cancer therapy.
- To optimize the photoswitchable HDACis for activation by less harmful green light.
Main Methods:
- Synthesis of azobenzene derivatives incorporating HDAC inhibitor scaffolds.
- Evaluation of enzyme inhibition activity in vitro under dark and illuminated conditions (UV and visible light).
- Assessment of cell viability in various cancer cell lines upon light activation.
Main Results:
- Initial HDACis showed >50-fold increased activity under UV light compared to the dark.
- Optimization introduced o-halogen atoms, shifting photoswitching to green light.
- Selected compounds demonstrated light-dependent reduction in cancer cell viability.
Conclusions:
- Developed photoswitchable HDACis with tunable activation wavelengths (UV to green light).
- Demonstrated light-controlled inhibition of enzyme activity and cancer cell proliferation.
- Contributed novel photoswitchable agents to the anticancer drug development toolbox.
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