The ubiquitin-proteasome system (UPS) is a key pathway involved in protein homeostasis via the regulation of intracellular protein levels. The application of proximity-induced biology to the UPS has given birth to proteolysis targeting chimeras (PROTACs), which are bifunctional molecules able to co-opt an E3 ligase for the ubiquitination and proteasome-dependent degradation of a selected protein. Targeted protein degradation (TPD) with PROTACs is now established as a disruptive modality both in chemical biology and drug discovery as it allows the efficient knockdown of an intracellular protein with a small molecule in a catalytic manner. With their unique mode of action and modular synthesis, PROTACs are being developed as therapeutics for various human diseases.
In order to enable discrete control over PROTACs function, our first investigation used light as a precision tool for the spatiotemporal activation of caged and photoswitchable degraders. The design, synthesis, photochemistry, and cellular activity of novel light-activated PROTACs is reported. Furthermore, with the ambition to apply such tools in vivo, non-conventional light sources were explored to activate the degraders and overcome the limitations of ultraviolet and visible light. In a second approach, variation in intracellular oxygen concentration was used as a means to selectively activate PROTACs. Incorporation of a bioreductive unit on a degrader followed by testing in a hypoxic environment is presented.
In summary, this thesis describes our investigation towards the conditional control of TPD with newly designed bifunctional degraders which may help better study and tackle disease-relevant proteins.