Gary Tin, Marko Cigler, Matthias Hinterndorfer, Kevin D. Dong, Hana Imrichova, Steven P. Gygi, Georg E. Winter,
Bioorganic & Medicinal Chemistry Letters, 2024
https://doi.org/10.1016/j.bmcl.2024.129779
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.
