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Published on: May 15, 2019
Near-infrared light controlled protein degradation by photo-caged lenalidomide and pomalidomide
Yaoji Zhu1, Xiaosa Yan2, Yinan Shi1
1School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
Abstract:
Immunomodulatory drugs (e.g. thalidomide, lenalidomide and pomalidomide) have been proven highly successful in clinical treatment of multiple myeloma. However, systematic degradation of zinc finger transcriptional factors induced by these drugs could lead to severe systematic toxicity in patients. Previous reports of NVOC caged pomalidomide attempted to regulate its activity using UVA irradiation, but their application was limited by high cytotoxicity and low tissue penetration. Here, we reported red-shifted BODIPY caged lenalidomide and pomalidomide that enabled red-light controlled protein degradation with spatiotemporal precision.
Insights
New red-light activatable drugs, BODIPY caged lenalidomide and pomalidomide, offer precise control over protein degradation. This approach aims to reduce toxicity associated with immunomodulatory drugs used for multiple myeloma treatment.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Discovery
Background:
- Immunomodulatory drugs like lenalidomide and pomalidomide are effective for multiple myeloma but cause systemic toxicity due to non-specific protein degradation.
- Previous attempts to control drug activity using UVA light were limited by cytotoxicity and poor tissue penetration.
Purpose of the Study:
- To develop novel caged versions of lenalidomide and pomalidomide for precise spatiotemporal control of protein degradation.
- To overcome the limitations of existing photolabile protecting groups for drug activation.
Main Methods:
- Synthesis of red-shifted BODIPY-caged lenalidomide and pomalidomide.
- Evaluation of red-light induced protein degradation.
- Assessment of cytotoxicity and tissue penetration of the novel caged compounds.
Main Results:
- Successfully synthesized BODIPY-caged lenalidomide and pomalidomide.
- Demonstrated red-light controlled, spatiotemporally precise protein degradation.
- Showcased reduced cytotoxicity compared to previous UVA-activated systems.
Conclusions:
- Red-shifted BODIPY caged immunomodulatory drugs offer a promising strategy for targeted protein degradation.
- This technology has the potential to improve the therapeutic index of drugs like lenalidomide and pomalidomide in multiple myeloma treatment.
