High-resolution structures of the bound effectors avadomide (CC-122) and iberdomide (CC-220) highlight advantages and limitations of the MsCI4 soaking system

Christopher Heim,Marcus D. Hartmann

doi:10.1107/s2059798322000092

Abstract

Cereblon (CRBN) is the substrate receptor of the CRL4CRBN E3 ubiquitin ligase and is a central player in targeted protein degradation. It is the target of the thalidomide-derived immunomodulatory drugs (IMiDs) and is one of the most widely employed receptors for proteolysis-targeting chimeras (PROTACs), both of which induce the ubiquitination and subsequent proteasomal degradation of target proteins. Structural studies of ligand binding to CRBN are crucial to elucidate the mechanisms of action and for mediation of side effects, ultimately aiding the development of next-generation IMiDs and PROTACs. With this aim, a crystal-soaking system based on the single-domain bacterial homologue MsCI4 has previously been established and used to delineate the binding modes of several classes of small molecules, including FDA-approved drugs, at the molecular level. Here, this system was used to characterize the binding of the next-generation IMiDs avadomide (CC-122) and iberdomide (CC-220) at high resolution, highlighting the advantages and limitations of the MsCI4 system and its implications for the development of future cereblon effectors.

Highlights

Thalidomide-derived immunomodulatory drugs (IMiDs) have been indispensable in the treatment of various diseases such as erythema nodosum leprosum (Walker et al, 2007), myelodysplastic syndromes (Kale & List, 2006; Bertolini et al, 2001) and most notably various forms of multiple myeloma (MM; Rajkumar et al, 2005; Bjorklund et al, 2020; Cruz, 2016; Kronke et al, 2014)
CRBN serves as the substrate receptor of the CUL4–RBX1–DDB1–CRBN (CRL4CRBN) E3 ubiquitin ligase complex, where it is responsible for the recognition of endogenous substrates, including glutamine synthetase (Nguyen et al, 2016, 2017) and MEIS2 (Fischer et al, 2014)
MsCI4 crystals can be grown reproducibly under a variety of conditions and generally diffract to high resolution, even after extensive soaking trials. This soaking system has proven to be a reliable surrogate system to determine the binding of many small molecules, ranging from low-affinity to high-affinity binders, including immunomodulatory drugs, their analogues and hydrolysis products, and a variety of FDA-approved drugs, at high resolution

Summary

Introduction

Thalidomide-derived immunomodulatory drugs (IMiDs) have been indispensable in the treatment of various diseases such as erythema nodosum leprosum (Walker et al, 2007), myelodysplastic syndromes (Kale & List, 2006; Bertolini et al, 2001) and most notably various forms of multiple myeloma (MM; Rajkumar et al, 2005; Bjorklund et al, 2020; Cruz, 2016; Kronke et al, 2014). All current IMiDs rely on the same glutarimide moiety for binding to CRBN, while the remainder of the molecule is unique to each IMiD. These unique moieties protrude into the solvent upon binding to CRBN, thereby mediating different neo-substrate specificities, which accounts for most of the efficacy of IMiDs

Methods

Results

Conclusion