Structural rationalization of GSPT1 and IKZF1 degradation by thalidomide molecular glue derivatives

Abstract

Thalidomide and its derivatives are molecular glues that bind cereblon (CRBN), a component of an E3 ubiquitin ligase complex, and mediate protein interactions with neosubstrates resulting in their polyubiquitination and...

Development of sulfonyl fluoride chemical probes to advance the discovery of cereblon modulators

“…4). Pleasingly, CPD-2743 also retained IKZF1 degradation capacity, again, with weaker effects than the isoindolinone iberdomide, but similar to EM12 (DC 50 193 ± 52 nM, D max 66%) 19 in line with our original hypothesis (Fig. 4).…”

Targeted protein degradation in CNS disorders: a promising route to novel therapeutics?

“…However, the determinative power of these MPOs was weak across much of the chemical space surveyed. The observation that CRBN ligands extend the PPI surface ( Oleinikovas et al, 2024 ), and can cause PPI relevant conformational changes ( Watson et al, 2022 ) is consistent with groups apparently distal from the common binding site influencing substrate selectivity ( Nowak et al, 2023 ; Nguyen et al, 2024 ). In studies of CRBN binders it was observed that more proteins interact than are degraded ( Sievers et al, 2018 ) an effect which may give rise to stronger selectivity in cells ( Oleinikovas et al, 2024 ).…”

Photoswitchable Molecular Glues Enable Optical Control of Transcription Factor Degradation

“…Recently, we demonstrated reduced off-targets with 5-substituted degraders, [24] and another recent study shows that blocking the 5-position of the phthalimide in the IMiD scaffold prevents the formation of toxic 5-OH metabolites. [25] Taken together, these data suggest that the 5-substituted phthalimide of PHOIMiD-9 reduces off-target degradation relative to pomalidomide. These results are consistent with structure-activity relationships from other studies that have found reduced off-targets profiles associated with 5-substituted degraders.…”