Thalidomide-O-C8-NH2 hydrochloride

Background Introduction

Thalidomide-O-C8-NH2 hydrochloride is a versatile E3 ligase ligand-linker conjugate based on the thalidomide pharmacophore. This compound harnesses the ability of thalidomide derivatives to recruit the cereblon (CRBN) E3 ubiquitin ligase, making it an essential building block for PROTAC (Proteolysis Targeting Chimera) and molecular glue development. The introduction of an optimal C8 alkyl chain with a terminal amine provides a functional handle for chemical conjugation, broadening its utility in targeted protein degradation research.

Mechanism

The mechanism of action for Thalidomide-O-C8-NH2 hydrochloride involves its specific binding to the cereblon (CRBN) E3 ubiquitin ligase substrate receptor. In PROTAC design, the thalidomide moiety serves as the E3 ligase recruiting element. The flexible C8 linker, terminating in a primary amine, allows for the facile attachment to a ligand for a target protein. When incorporated into a PROTAC molecule, Thalidomide-O-C8-NH2 hydrochloride facilitates the formation of a ternary complex between the E3 ligase and the protein of interest. This results in ubiquitination and proteasomal degradation of the target protein, promising enhanced selectivity and potency in drug development.

Applications

Thalidomide-O-C8-NH2 hydrochloride is widely utilized in the synthesis of PROTACs and molecular glues aimed at degrading challenging protein targets implicated in cancer, neurodegeneration, and other diseases. Researchers use this ligand-linker conjugate to couple with various protein-targeting warheads, enabling rapid assembly and optimization of heterobifunctional molecules. It is also valuable in structure-activity relationship (SAR) studies, screening for highly efficient degrader molecules, and expanding the chemical toolbox for targeted protein degradation platforms in drug discovery.

• Extended C8 alkyl chain improves linker flexibility and spatial orientation for efficient PROTAC design.
• Amine terminal group enables reliable conjugation with various warheads, ideal for targeted protein degradation via the CRBN pathway.