Lessons in PROTAC design from selective degradation with a promiscuous warhead (2017, background): “…E3 ubiquitin ligase commonly used in PROTAC design is Cereblon (CRBN), which is the substrate adapter for the Cullin 4a E3 ligase complex whose endogenous substrates have not been fully characterized, but likely include MEIS2 and glutamine synthetase (Fischer et al., 2014; Nguyen et al., 2016).”
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. (2015, methodology): “To circumvent these limitations, we designed a hetero-bifunctional molecule, ARV-825, by connecting a small-molecule BRD4 binding moiety (OTX015) to an E3 ligase cereblon binding moiety (pomalidomide) using PROTAC technology (Boi et al., 2015; Fischer et al., 2014; Ito et al., 2010).”
Proteolysis Targeting Chimeras as Therapeutics and Tools for Biological Discovery (2020, unknown): “The off-target effects of CRBN-recruiting PROTACs must be very carefully assessed, since the IMiD components, alone or incorporated into PROTACs, can induce the degradation of zinc finger CRBN neo-substrates (Fischer et al., 2014; Ishoey et al., 2018; Krönke et al., 2014; Matyskiela et al., 2016).”
Thalidomide‐induced teratogenesis: History and mechanisms (2015, background): “Indeed these studies further suggest that several targets could be prevented from binding the E3 ubiquitination complex and thus not be degraded, including Meis2, a gene involved in proximal limb development (Fischer et al., 2014).”
Structural Dynamics of the Cereblon Ligand Binding Domain (2015, background): “This structure [8] is bound to lenalidomide and is in a virtually identical conformation to the structures of chicken cereblon in complex with thalidomide, lenalidomide or pomalidomide [9].”