Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers

Trads, Julie; Hüll, Katharina; Matsuura, Bryan S.; Laprell, Laura; Fehrentz, Timm; Görldt, Nicole; Kozek, Krystian A.; Weaver, C. David; Klöcker, Nikolaj; Barber, David G.; Trauner, Dirk

doi:10.26434/chemrxiv.8014580

Cited by 2 publications

(1 citation statement)

References 19 publications

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“…However, the impact of linker conformation on PROTAC activity is not fully un derstood. We therefore explored both regular azobenzenes (more sta ble in their trans form) and diazocines (more stable in cis) (27,28).…”

Section: Introductionmentioning

confidence: 99%

PHOTACs enable optical control of protein degradation

et al. 2020

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PROTACs (PROteolysis TArgeting Chimeras) are bifunctional molecules that target proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins. We now introduce photoswitchable PROTACs that can be activated with the spatiotemporal precision that light provides. These trifunctional molecules, which we named PHOTACs (PHOtochemically TArgeting Chimeras), consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated with different wavelengths of light. Our modular approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity. RESULTS Design, synthesis, and photophysical characterizationThe design of our PHOTACs was guided by a desire to render our molecules as diversifiable and modular as possible while ensuring

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Section: Introductionmentioning

confidence: 99%

PHOTACs enable optical control of protein degradation

et al. 2020

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In Situ Observation of Photoswitching by NMR Spectroscopy: A Photochemical Analogue to the Exchange Spectroscopy Experiment

et al. 2019

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We present 1D and 2D NMR experiments that provide in situ insights into photoinduced isomerizations. Irradiation during the mixing period of an exchange spectroscopy (EXSY) experiment leads to characteristic cross peaks in 2D spectra. The phototriggered exchange of magnetization occurring in photoswitchable (Z)-and (E)isomers of three selected azo compounds provides information on the dynamic E/Z equilibria. We report the dependence of the diagonal-to-cross-peak ratio on concentration, light intensity, and mixing time. In analogy to exchange spectroscopy, this ratio mirrors the efficiency of light induced molecular transformations. Furthermore, we present a time-saving 1D version and a combined light/phase cycle scheme for enhanced detectability of photoinduced changes in the spectrum. This insight into light-induced structural changes is highly suited to study macromolecules, in which photoswitchable units trigger conformational changes.

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Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers

Cited by 2 publications

References 19 publications

PHOTACs enable optical control of protein degradation

PHOTACs enable optical control of protein degradation

In Situ Observation of Photoswitching by NMR Spectroscopy: A Photochemical Analogue to the Exchange Spectroscopy Experiment

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