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An Integrated System to Remotely Trigger Intracellular Signal Transduction by Upconversion Nanoparticle-mediated Kinase Photoactivation
Published on: August 30, 2017
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.
Abstract:
The cytochrome P450 family of enzymes (CYPs) are important targets for medicinal chemistry. Recently, CYP1B1 has emerged as a key player in chemotherapy resistance in the treatment of cancer. This enzyme is overexpressed in a variety of tumors, and is correlated with poor treatment outcomes; thus, it is desirable to develop CYP1B1 inhibitors to restore chemotherapy efficacy. However, possible off-target effects, such as inhibition of liver CYPs responsible for first pass metabolism, make selective inhibition a high priority to avoid possible drug-drug interactions and toxicity. Here we describe the creation of light-triggered CYP1B1 inhibitors as "prodrugs", and achieve >6000-fold improvement in potency upon activation with low energy (660 nm) light. These systems provide a selectivity index of 4,000-100,000 over other off-target CYPs. One key to the design was the development of coordinating CYP1B1 inhibitors, which suppress enzyme activity at pM concentrations in live cells. The metal binding group enforces inhibitor orientation in the active site by anchoring to the iron. The second essential component was the biologically compatible Ru(II) scaffold that cages the inhibitors before photochemical release. These Ru(II) photocages are anticipated to provide similar selectivity and control for any coordinating CYP inhibitors.
Insights
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.
