The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron

Accessing three-branched high-affinity cereblon ligands for molecular glue and protein degrader design

“…[10][11][12][13][14][15] Recently, a new class of CRBN ligands has been coined, i.e. CRBN E3 ligase modulators (CELMoDs), which are typically based on aminoglutarimide as the core binding moiety, [17][18][19][20][21] and to which examples such as iberdomide (CC-220, Figure 1) and mezigdomide (CC-92480) belong. 16,22,23 The structural elongation in iberdomide compared to lenalidomide enabled additional interactions with CRBN or ligase substrates leading to a more pronounced degradation of the CRBN neosubstrates, namely the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3).…”

“…[10][11][12][13][14][15] Recently, a new class of CRBN ligands has been coined, i.e. CRBN E3 ligase modulators (CELMoDs), which are typically based on aminoglutarimide as the core binding moiety, [17][18][19][20][21] and to which examples such as iberdomide (CC-220, Fig. 1) and mezigdomide (CC-92480) belong.…”

E3 Ligases Meet Their Match: Fragment-Based Approaches to Discover New E3 Ligands and to Unravel E3 Biology

“…116 Akin to the recognition of its exogenous ligands, it has recently been shown that CRBN recognizes the C-terminal cyclic imide post-translational modification as a protein damage degron motif. 117,118 Building on earlier work that described the binding of uridine to CRBN, 119 Boichenko et al took a knowledge-based approach to explore what they referred to as the "chemical ligand space of CRBN". 120 Noting the similarities between uridine's and thalidomide's uracil and glutarimide rings, respectively, they employed a FRET assay to screen a vast selection of a 4−7 membered ring matched molecular pair (MMP) fragments to reveal the key pharmacophores for CRBN binding (Figure 10).…”

“…CRBN has become a focal point in UPS research since it was recognized as the protein that the immunomodulatory imide drugs (IMiDs) , thalidomide, pomalidomide, and lenalidomide bind to in order to elicit their therapeutic effect via a molecular glue mechanism of action (MOA). − It has also become infamous following the characterization of its role in thalidomide-induced teratogenicity in the unborn child, , arguably one of the pharmaceutical industry’s most significant tragedies to date. , Furthermore, since the advent of the PROTAC modality in the medicinal chemistry community, the ubiquity of CRBN binding motifs in research papers and patent applications is noteworthy . Akin to the recognition of its exogenous ligands, it has recently been shown that CRBN recognizes the C-terminal cyclic imide post-translational modification as a protein damage degron motif. , …”

Life mimics art

“…1). 9 They highlighted that cyclization of glutamine or asparagine at the C-terminus of a protein might arise either through the action of enzymes or spontaneous cyclization during protein ageing or specific protein splicing events. Thus, to identify the minimum structural degron motif, the authors designed several ligands mimicking thalidomide that could functionally engage cereblon in cells.…”