Proteolysis targeting chimeras (PROTACs) are an emerging field of therapeutics which have shown great promise as potential drug candidates. These compounds consist of a target protein binder connected via a linker to an E3 ligase binding motif, which can hijack the ubiquitin proteasome system to degrade this target protein in a cellular environment. Recently, PROTACs have been shown to degrade a variety of proteins using different E3 ligases with low nanomolar potencies. Herein, we describe the synthesis, photophysical characterisation, and biological activity of a series of novel photoswitchable PROTACs, primarily targeting the androgen receptor. Incorporation of a photoswitchable moiety in pharmaceutical entities has been shown to mitigate off-target toxicity, thus becoming a promising strategy to reduce attrition rates in drug discovery. By dosing an inactive drug and using light to modulate its biological activity at the site of action, we can deliver improved selectivity, efficacy, and overall safety profile. Our photoswitchable PROTACs incorporate an ortho-fluoroazobenzene linker, resulting in distinct E and Z conformations which can be selectively interconverted using different wavelengths of visible light. We expect these conformations to differ in their biological profiles due to their significant structural differences, leading to an active and inactive form. By combining photopharmacology with PROTACs, we hope to deliver a novel series of drugs with an improved therapeutic index.

Photoswitchable PROTACs: Visible light activated degradation of the androgen receptor

2019 Fall National Meeting

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