Light-activatable photochemically targeting chimeras (PHOTACs) enable the optical control of targeted protein degradation of HDAC6

  • RSC Med Chem. 2025 Mar 13. doi: 10.1039/d4md00972j.
Silas L Wurnig  1 ,  Maria Hanl  1 ,  Thomas M Geiger  2 ,  Shiyang Zhai  1 ,  Ina Dressel  2 ,  Dominika E Pieńkowska  2 ,  Radosław P Nowak  2 ,  Finn K Hansen  1
Affiliations
  • 1. Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn An der Immenburg 4 53121 Bonn Germany [email protected].
  • 2. Institute of Structural Biology, Medical Faculty, University of Bonn Venusberg Campus 1 53127 Bonn Germany.
PMID: 40135143 DOI: 10.1039/d4md00972j
Abstract

Proteolysis targeting chimeras (PROTACs) are heterobifunctional modalities that induce protein degradation via a catalytic mode of action. Photochemically targeting chimeras (PHOTACs) are a subset of PROTACs designed for light-activated protein degradation, thereby offering precise spatiotemporal control. In this study, we report the design, solid-phase synthesis, and characterization of the first PHOTACs targeting histone deacetylase 6 (HDAC6). We achieved this by incorporating an azobenzene photoswitch into our previously developed HDAC6-selective PROTAC A6. Among the synthesized compounds, PHOTAC 12 demonstrated no HDAC6 degradation in the absence of light but showed significant degradation upon activation to its cis-state with 390 nm light irradiation. Notably, we find that PHOTAC 12 in the cis-state shows significantly improved ternary complex formation compared to the trans-state correlating with its degradation efficacy. Overall, PHOTAC 12 is a promising lead compound for the development of light-activatable HDAC6 degraders.

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