The cyclimids: Degron-inspired cereblon binders for targeted protein degradation

Saki Ichikawa; N Connor Payne; Wenqing Xu; Chia-Fu Chang; Nandini Vallavoju; Spencer Frome; Hope A Flaxman; Ralph Mazitschek; Christina M Woo

doi:10.1016/j.chembiol.2024.01.003

The cyclimids: Degron-inspired cereblon binders for targeted protein degradation

Cell Chem Biol. 2024 Jan 31:S2451-9456(24)00039-4. doi: 10.1016/j.chembiol.2024.01.003. Online ahead of print.

Authors

Saki Ichikawa¹, N Connor Payne², Wenqing Xu¹, Chia-Fu Chang¹, Nandini Vallavoju¹, Spencer Frome¹, Hope A Flaxman¹, Ralph Mazitschek³, Christina M Woo⁴

Affiliations

¹ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
² Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
³ Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: ralph@broadinstitute.org.
⁴ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: cwoo@chemistry.harvard.edu.

PMID: 38320555
DOI: 10.1016/j.chembiol.2024.01.003

Abstract

Cereblon (CRBN) is an E3 ligase substrate adapter widely exploited for targeted protein degradation (TPD) strategies. However, achieving efficient and selective target degradation is a preeminent challenge with ligands that engage CRBN. Here, we report that the cyclimids, ligands derived from the C-terminal cyclic imide degrons of CRBN, exhibit distinct modes of interaction with CRBN and offer a facile approach for developing potent and selective bifunctional degraders. Quantitative TR-FRET-based characterization of 60 cyclimid degraders in binary and ternary complexes across different substrates revealed that ternary complex binding affinities correlated strongly with cellular degradation efficiency. Our studies establish the unique properties of the cyclimids as versatile warheads in TPD and a systematic biochemical approach for quantifying ternary complex formation to predict their cellular degradation activity, which together will accelerate the development of ligands that engage CRBN.

Keywords: CoraFluor; E3 ligase; PROTAC; TR-FRET; cereblon; cyclimids; degrader; targeted protein degradation assay; ternary complex.