Discovery of a DCAF11-dependent cyanoacrylamide-containing covalent degrader of BET-proteins
Gary Tin, Marko Cigler, Matthias Hinterndorfer, Kevin Dong, Hana Imrichová, Steven P. Gygi, Georg E. Winter
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.