Figure 1.
Overview of IMiD mechanism of action, the investigated compounds and reported CRBN mutations. (A) Schematic of the CRL4CRBN E3 ubiquitin ligase complex and the IMiD mechanism of action that results in myeloma cell cytotoxicity. Figure created with BioRender.com. (B) Chemical structures for Len, Pom, iberdomide (CC-220), and Mezi (CC-92480). Len and Pom share a common glutarimide ring and differ only through the replacement of the isoindolinone in Len by a phthalimide in Pom.9 This difference leads to altered neosubstrate degradation, with Len being the only one able to potently degrade the kinase CK1α in cells.10 The chemical composition of the next-generation CELMoDs has led to higher CRBN-binding affinity. Iber achieves that through its additional phenyl and morpholino moieties, which extend the interactions with the β-hairpin sensor loop resulting in enhanced stabilization of the closed conformation of CRBN and ultimately increased neosubstrate ubiquitination and degradation.2,11 The design of Mezi further improves this by creating additional interactions with CRBN, which results in a further improvement in the degradation efficiency and kinetics.4,11 (C) Linear depiction of the CRBN protein; above are noted all CRBN mutations (n = 34) that have been reported in patients and below CRBNs are the 12 mutations investigated in this study. The color of the mark denotes the type of each mutation. Regarding mutation p,W415X, Gooding et al23 reported this mutation as W415X. Among the potential reported mutations for this region, it was selected to mutate Trp (W) into a Gly (G) as the most potentially harmful to proper folding and stability of CRBN due to the size difference of these residues. Figure generated using the ProteinPaint https://proteinpaint.stjude.org/ software by St. Jude Children’s Research Hospital. ∗Mutation not encountered in patients but added as an experimental positive control. One of the 3 Trp forming the IMiDs binding pocket, its mutation to an alanine has been previously demonstrated to functionally inactivate CRBN.7,13

Overview of IMiD mechanism of action, the investigated compounds and reported CRBN mutations. (A) Schematic of the CRL4CRBN E3 ubiquitin ligase complex and the IMiD mechanism of action that results in myeloma cell cytotoxicity. Figure created with BioRender.com. (B) Chemical structures for Len, Pom, iberdomide (CC-220), and Mezi (CC-92480). Len and Pom share a common glutarimide ring and differ only through the replacement of the isoindolinone in Len by a phthalimide in Pom.9 This difference leads to altered neosubstrate degradation, with Len being the only one able to potently degrade the kinase CK1α in cells.10 The chemical composition of the next-generation CELMoDs has led to higher CRBN-binding affinity. Iber achieves that through its additional phenyl and morpholino moieties, which extend the interactions with the β-hairpin sensor loop resulting in enhanced stabilization of the closed conformation of CRBN and ultimately increased neosubstrate ubiquitination and degradation.2,11 The design of Mezi further improves this by creating additional interactions with CRBN, which results in a further improvement in the degradation efficiency and kinetics.4,11 (C) Linear depiction of the CRBN protein; above are noted all CRBN mutations (n = 34) that have been reported in patients and below CRBNs are the 12 mutations investigated in this study. The color of the mark denotes the type of each mutation. Regarding mutation p,W415X, Gooding et al23 reported this mutation as W415X. Among the potential reported mutations for this region, it was selected to mutate Trp (W) into a Gly (G) as the most potentially harmful to proper folding and stability of CRBN due to the size difference of these residues. Figure generated using the ProteinPaint https://proteinpaint.stjude.org/ software by St. Jude Children’s Research Hospital. ∗Mutation not encountered in patients but added as an experimental positive control. One of the 3 Trp forming the IMiDs binding pocket, its mutation to an alanine has been previously demonstrated to functionally inactivate CRBN.7,13 

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