Thalidomide-CH2CONH-C3-COOH

Background Introduction

Thalidomide-CH2CONH-C3-COOH is a small-molecule E3 ligase ligand-linker conjugate designed for use in targeted protein degradation technologies, such as PROTACs (Proteolysis Targeting Chimeras). Based on thalidomide, a well-characterized ligand for the Cereblon (CRBN) E3 ubiquitin ligase, this molecule incorporates a specialized linker and functional group (carboxylic acid) for easy conjugation. The thalidomide-core grants selective CRBN engagement, essential for designing next-generation protein degraders.

Mechanism

The mechanism of Thalidomide-CH2CONH-C3-COOH centers around targeted ubiquitination. Upon incorporation into a bifunctional molecule, the thalidomide moiety recruits the CRBN E3 ubiquitin ligase complex. The incorporated linker (CH2CONH-C3) provides optimal spatial separation between the E3 ligase and the target protein ligand, minimizing steric hindrance. The carboxylic acid group at the terminus allows for efficient chemical conjugation with various target protein binding warheads. This design enables the subsequent assembly of PROTACs, which facilitate the transfer of ubiquitin tags to the target protein, marking it for rapid degradation by the proteasome.

Applications

Thalidomide-CH2CONH-C3-COOH is widely used in the development of PROTACs and molecular glues that exploit the CRBN E3 ligase pathway. It serves as a modular building block for synthesizing customized protein degraders targeting disease-related proteins, such as kinases, transcription factors, or oncoproteins. Researchers leverage this conjugate to expand their chemical toolbox for drug discovery, mechanistic studies, and the development of next-generation therapeutics for cancer, neurodegeneration, and autoimmune diseases. With its versatile linker and high ligase affinity, Thalidomide-CH2CONH-C3-COOH facilitates rapid construction of PROTAC libraries, streamlining structure-activity relationship (SAR) studies and accelerating the optimization of targeted protein degraders.

• Carboxylic acid functionality enables versatile conjugation to various warheads and linkers, enhancing PROTAC design flexibility.
• Optimized for effective recruitment of CRBN E3 ligase, facilitating efficient targeted protein degradation in PROTAC applications.