2. Academic Validation
  3. Discovery of a DCAF11-dependent cyanoacrylamide-containing covalent degrader of BET-proteins

Discovery of a DCAF11-dependent cyanoacrylamide-containing covalent degrader of BET-proteins

  • Bioorg Med Chem Lett. 2024 Jul 15:107:129779. doi: 10.1016/j.bmcl.2024.129779.
Gary Tin 1,  Marko Cigler 2,  Matthias Hinterndorfer 1,  Kevin D Dong 3,  Hana Imrichova 1,  Steven P Gygi 3,  Georg E Winter 4
Affiliations

Affiliations

  • 1 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 2 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. Electronic address: MCigler@cemm.oeaw.ac.at.
  • 3 Department of Cell Biology, Harvard Medical School, Boston, USA.
  • 4 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. Electronic address: GWinter@cemm.oeaw.ac.at.
PMID: 38729317 DOI: 10.1016/j.bmcl.2024.129779
Abstract

Targeted protein degradation is mediated by small molecules that induce or stabilize protein-protein interactions between targets and the ubiquitin-proteasome machinery. Currently, there remains a need to expand the repertoire of viable E3 Ligases available for hijacking. Notably, covalent chemistry has been employed to engage a handful of E3 Ligases, including DCAF11. Here, we disclose a covalent PROTAC that enables DCAF11-dependent degradation, featuring a cyanoacrylamide warhead. Our findings underscore DCAF11 as an interesting candidate with a capacity to accommodate diverse electrophilic chemistries compatible with targeted protein degradation.

Keywords

Cyanoacrylamide-based PROTACs; DCAF11; Targeted protein degradation.

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