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

Abstract

The Petasis borono-Mannich reaction was employed for an alternative entry towards three-branched cereblon ligands. Such compounds are capabable of making multiple interactions with the protein surface and possess a suitable...

Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs

“…However, the interplay with Asn351 can be restored by attaching an amide group to the core binding moieties of aminosuccinimide or aminoglutarimides, as exemplified by thalidomide hydrolysis products that maintained CRBN affinity. 23,24 Intriguingly, we and others recently reported this particular minimal binding motif to be identical to a natural degron that interacts with CRBN (V, Figure 1). [30][31][32] Based on these studies on minimal CRBN ligands and the medicinal chemistry-driven optimization of a benzamide-type screening hit, we have obtained attractive non-phthalimide CRBN binders for PROTAC design.…”

“…1.17 g (80%); mp 233-236 °C; Rf = 0.25 (CH2Cl2/MeOH 20:1); 23.99, 30.96, 49.37, 120.86, 124.98, 128.38, 137.69, 142.76, 147.70, 167.59, 171.84, 173.00; UPLC-retention time: 30.90, 49.92, 56.76, 107.13, 115.42, 128.88, 131.43, 149.69, 157.31, 163.58, 171.92, 172.95 26, 30.82, 49.45, 111.59, 113.84, 121.71, 130.76, 131.50, 151.47, 166.25, 172.19, 173. 23,30.97,49.44,110.84 (d,J = 5.3 Hz),115.46,122.33,124.02 (q, J = 274.6 Hz), 127.71 (q, J = 31.0 Hz), 130. 28, 150.38, 167.51, 172.15, 173.11 4-Amino-N- (2,6-dioxo-3-piperidyl)-2-methyl-benzamide (11c).…”

“…Our labs are interested in advancing E3 ligase ligands and have contributed in various ways to explore their structure-activity relationships within PROTAC design. 14,18,[23][24][25] CRBN ligands rely on only a small set of interactions that are classically limited to H-bonds of the glutarimide moiety within the conserved tri-tryptophan pocket and a further H-bond between one of the phthalimide carbonyls and a conserved asparagine (Asn351) in the sensor loop. 26,27 We and others have suggested that simplifying classical phthalimide-based ligands can further improve the suitability of CRBN-hijacking probes.…”

Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs

“…Similar to the newly reported phenyl glutarimide- and phenyl dihydrouracil-based ligands, these reporters rely mainly on interactions within the tri-tryptophan pocket, but do not interact with Asn351 as phthalimide-based ligands do. However, the interplay with Asn351 can be restored by attaching an amide group to the core binding moieties of aminosuccinimide or aminoglutarimides, as exemplified by thalidomide hydrolysis products that maintained CRBN affinity. , Intriguingly, we and others recently reported this particular minimal binding motif to be identical to a natural degron that interacts with CRBN ( V , Figure ). − Based on these studies on minimal CRBN ligands and the medicinal chemistry-driven optimization of a benzamide-type screening hit, we have obtained attractive nonphthalimide CRBN binders for PROTAC design.…”

“…Our laboratories are interested in advancing E3 ligase ligands and have contributed in various ways to explore their structure–activity relationships within PROTAC design. ,,− CRBN ligands rely on only a small set of interactions that are classically limited to H-bonds of the glutarimide moiety within the conserved tri-tryptophan pocket and a further H-bond between one of the phthalimide carbonyls and a conserved asparagine (Asn351) in the sensor loop. − We and others have suggested that simplifying classical phthalimide-based ligands can further improve the suitability of CRBN-hijacking probes. For instance, in 2016, we described a novel FRET reporter for the characterization of CRBN ligands based on a minimal uracil scaffold .…”