Controlling PROTACs with Light. (2nd July 2020)

• Record Type: Journal Article
• Authors: Verma, Shreya; Manna, Debasish
• Is Part Of: ChemMedChem. Volume 15:Number 14(2020)
• Page Start: 1258
• Page End: 1261
• Publication Date: 2020-07-02
• Subjects: azobenzenes -- irradiation -- photocages -- protein degradation -- UV light; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000249
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Proteolysis targeting chimeras, PROTACs, are emerging as a powerful strategy for exerting exogenous control over protein levels, allowing small molecules to exploit the ubiquitin–proteasome pathway for targeted protein degradation. This highlight focuses on the fusion of photochemistry with these bifunctional compounds, which has provided a novel pathway for spatiotemporally tuning the activation of PROTACs in the form of their photocaged and photoswitchable versions. Photocaged PROTACs consist of a hindered optolabile group that detaches only upon irradiation at a specific wavelength, releasing the active PROTAC. These modified PROTACs are inactive in the dark. Photoswitchable PROTACs are photoisomerizable molecules with azobenzene linkages that are active in either the cis or trans form and inactive in the other. The isomers interconvert upon irradiation with an appropriate wavelength of light and relax to the thermodynamically stable isomer in the dark or with another wavelength of light. Although photocaged PROTACs only permit activation control for protein degradation, photoswitching PROTACs offer reversible activation and deactivation by using suitable wavelengths of light. Abstract : Casting a little light on protein degradation : The evolution of bifunctional PROTACs into their opto‐modulatory variants has opened mechanisms to acquire spatiotemporal control over PROTAC activation in vitro and in vivo . Photocaged and photoswitchable PROTACs are the two approaches that provide one‐ and two‐way regulation, respectively.