Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation

Targeted
protein degradation with proteolysis targeting chimeras
(PROTACs) is a powerful therapeutic modality for eliminating disease-causing
proteins through targeted ubiquitination and proteasome-mediated degradation.
Most PROTACs have exploited substrate receptors of Cullin-RING E3
ubiquitin ligases such as cereblon and VHL. Whether core, shared,
and essential components of the Cullin-RING E3 ubiquitin ligase complex
can be used for PROTAC applications remains less explored. Here, we
discovered a cysteine-reactive covalent recruiter EN884 against the
SKP1 adapter protein of the SKP1-CUL1-F-box containing the SCF complex.
We further showed that this recruiter can be used in PROTAC applications
to degrade neo-substrate proteins such as BRD4 and the androgen receptor
in a SKP1- and proteasome-dependent manner. Our studies demonstrate
that core and essential adapter proteins within the Cullin-RING E3
ubiquitin ligase complex can be exploited for targeted protein degradation
applications and that covalent chemoproteomic strategies can enable
recruiter discovery against these targets.