Friday, February 2, 2024

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

Seong Ho Hong, Anand Divakaran, Akane Osa, Oscar W. Huang, Ingrid E. Wertz, and Daniel K. Nomura
ACS Chemical Biology 2024

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.



Mutant-selective AKT inhibition through lysine targeting and neo-zinc chelation

Gregory B. Craven, Hang Chu, Jessica D. Sun, Jordan D. Carelli, Brittany Coyne, Hao Chen, Ying Chen, Xiaolei Ma, Subhamoy Das, Wayne Kong, A...