Photoactive Bifunctional Degraders: Precision Tools To Regulate Protein Stability.

Abstract

Targeted protein degradation with bifunctional degraders is positioned as a remarkable game-changing strategy to control cellular protein levels and promises a new therapeutic modality in drug discovery. Light activation of a degrader to achieve exquisite spatiotemporal control over protein stability in cells has attracted the interest of multiple research groups, with recent reports demonstrating optical control of proteolysis with chimeric molecules bearing photolabile or photoswitchable motifs. In this context of targeted proteolysis research spurring the emergence of innovative tools, we examine the design, synthesis, and properties of light-activated degraders. The significant impact of this approach in regulating disease-relevant protein levels in a light-dependent manner is highlighted with key examples, and future developments to fully harness the potential of light-induced protein degradation with photoactive bifunctional molecules are discussed.