Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands

Abstract

Proteolysis targeting chimeras (PROTACs) hijacking the cereblon (CRBN) E3 ubiquitin ligase have emerged as a novel paradigm in drug development. Herein we found that linker attachment points of CRBN ligands highly affect their aqueous stability and neosubstrate degradation features. This work provides a blueprint for the assembly of future heterodimeric CRBN-based degraders with tailored properties.

Development of Rapid and Facile Solid‐Phase Synthesis of PROTACs via a Variety of Binding Styles

“…Most of them contain an alkyl linker, [18,19,22] while others are based on a PEG linker, [23] a photoswitchable azobenzene type, [24] or dihydropyrazine [25] formed by cyclization of trans ‐cyclo‐octene with tetrazine. In the reported dBET1 and dBET6, thalidomide was used as the E3 ligand, but the C−O bond of thalidomide is possibly more unstable in buffer (pH 7.4) and human plasma than the C−N bond of pomalidomide [26] . Therefore, we decided to synthesize the pomalidomide‐type dBET ( PROTACs 5 – 7 , Scheme 2).…”

“…In the reported dBET1 and dBET6, thalidomide was used as the E3 ligand, but the CÀ O bond of thalidomide is possibly more unstable in buffer (pH 7.4) and human plasma than the CÀ N bond of pomalidomide. [26] Therefore, we decided to synthesize the pomalidomide-type dBET (PROTACs 5-7, Scheme 2). For the synthesis of PROTACs 5-7, in addition to 3azidopropylamine, 4-azidobutan-1-amine, and 8-azidooctan-1-amine were synthesized separately and used as starting linkers (Scheme S4, Supporting Information).…”

E3 ligase ligand chemistries: from building blocks to protein degraders

“…29 However, the additional amide bond might be disadvantageous concerning a higher topological polar surface area (TPSA) as well as increased hydrogen bond donor (HBD) or hydrogen bond acceptor (HBA) count, and sensitivity to hydrolysis. [69][70][71] Notably, the acetamide group in Example 11 (BSJ-03-123, Fig. 6) was found to massively reduce the binding of secondary CRBN substrates such as IKZF1 and might generally function to adjust this feature.…”

Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity

“…Generally, the nature and length of the linker and its connection points with both ligands greatly affect the stability of the complex molecule of the PROTACs [57][58][59][60].…”

“…Studies show that thalidomide [61] and its derivative pomalidomide can undergo nonenzymatic rapid hydrolysis at the four amide bonds of the phthalimide and glutarimide rings [57]. However, the stability of thalidomide derivatives as a component of a PROTAC molecule is significantly affected by the different linker junctions [57,58].…”