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

Abstract

Optimizing linker design is important for ensuring efficient degradation activity of proteolysis‐targeting chimeras (PROTACs). Therefore, developing a straightforward synthetic approach that combines the protein‐of‐interest ligand (POI ligand) and the ligand for E3 ubiquitin ligase (E3 ligand) in various binding styles through a linker is essential for rapid PROTAC syntheses. Herein, a solid‐phase approach for convenient PROTAC synthesis is presented. We designed azide intermediates with different linker lengths to which the E3 ligand, pomalidomide, is attached and performed facile PROTACs synthesis by forming triazole, amide, and urea bonds from the intermediates.

From classic medicinal chemistry to state‐of‐the‐art interdisciplinary medicine: Recent advances in proteolysis‐targeting chimeras technology

“…Xu et al. developed a method of solid‐phase organic synthesis 92 . They designed azide resins with different linkers to which the E3 ligand pomalidomide was pre‐attached, and they also developed similar amino and carboxyl resins.…”

“…91 Xu et al developed a method of solid-phase organic synthesis. 92 They designed azide resins with different linkers to which the E3 ligand pomalidomide was pre-attached, and they also developed similar amino and carboxyl resins. These resins can react with alkynyl, carboxyl, and amino groups of POI ligands to form complete PROTACs.…”

Capsule-based automated synthesis for the efficient assembly of PROTAC like molecules

“…Jiang 16 and Derksen 17 recently reported some insights on the synthesis of pomalidomide and lenalidomide-based PROTACs, building small libraries of PROTACs, which, thanks to carefully selected reaction conditions, typically had enhanced yields compared to similar reported structures. Although limited to a single class of E3 ligase ligands, Soural 18 and Demizu 19 reported interesting solid-phase approaches for the synthesis of PROTACs, which overcome most of the challenges associated with the use of classical solution-phase PROTAC synthesis. Despite these significant developments, all these approaches still need to be effected by highly specialized chemists with a deep knowledge of the field.…”

Solid‐Phase Synthesis of PROTACs and SNIPERs on Backbone Amide Linked (BAL) Resin

“…This involved the anchoring of pomalidomide via a linker to a functionalized aminomethyl polystyrene resin and subsequent elaboration. [6,7] Other CRBN targeting PROTACs prepared on solid-phase have been exemplified in the elaboration of solid-phase syntheses of HDAC inhibitors. [8,9] The Von Hippel-Lindau (VHL) E3 ligase ligand VH032 (Figure 1) has been widely used as a PROTAC template and solidphase techniques have been used in partial syntheses.…”