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An Integrated System to Remotely Trigger Intracellular Signal Transduction by Upconversion Nanoparticle-mediated Kinase Photoactivation
Published on: August 30, 2017
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Ru(II) photocages enable precise control over enzyme activity with red light
Dmytro Havrylyuk1, Austin C Hachey1, Alexander Fenton1
1Department of Chemistry, University of Kentucky, Lexington, KY, 40506, USA.
Nature Communications
|June 25, 2022
Summary
Researchers developed light-activated prodrugs targeting CYP1B1, an enzyme linked to chemotherapy resistance. These potent and selective inhibitors restore cancer treatment efficacy by overcoming off-target effects and toxicity concerns.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Cancer Biology
Background:
- Cytochrome P450 enzymes (CYPs) are crucial in drug metabolism and are key targets in medicinal chemistry.
- CYP1B1 is overexpressed in various cancers, contributing to chemotherapy resistance and poor patient outcomes.
- Selective inhibition of CYP1B1 is critical to enhance chemotherapy efficacy while minimizing off-target effects and drug-drug interactions.
Purpose of the Study:
- To design and synthesize novel light-triggered CYP1B1 inhibitors as prodrugs.
- To achieve high potency and selectivity for CYP1B1 inhibition upon photoactivation.
- To develop a controllable system for restoring chemotherapy efficacy.
Main Methods:
- Development of coordinating CYP1B1 inhibitors with a metal-binding group for precise active site orientation.
- Utilizing a ruthenium(II) (Ru(II)) scaffold as a photocage to control inhibitor release.
- Activation of prodrugs using low-energy visible light (660 nm).
Main Results:
- Achieved >6000-fold improvement in inhibitor potency upon light activation.
- Demonstrated high selectivity for CYP1B1, with selectivity indices ranging from 4,000 to 100,000 over other off-target CYPs.
- Coordinating inhibitors suppressed CYP1B1 activity at picomolar concentrations in live cells.
Conclusions:
- Light-triggered CYP1B1 inhibitors offer a promising strategy to overcome chemotherapy resistance.
- The Ru(II) photocage system provides excellent control and selectivity for CYP inhibition.
- This approach holds potential for developing targeted cancer therapies with reduced toxicity.
