Pomalidomide-C8-COOH

Background Introduction

Pomalidomide-C8-COOH is a specialized E3 ligase ligand-linker conjugate commonly utilized in the design and synthesis of proteolysis targeting chimeras (PROTACs). Pomalidomide is an analog of thalidomide belonging to the class of immunomodulatory drugs (IMiDs), widely recognized for its high affinity binding to the E3 ubiquitin ligase cereblon (CRBN). The addition of an 8-carbon linker terminating in a carboxylic acid (C8-COOH) provides essential chemical flexibility for coupling with various targeting ligands, thereby enabling the development of personalized protein degradation tools.

Mechanism

The mechanism of action for Pomalidomide-C8-COOH stems from its role as a bifunctional PROTAC building block. The pomalidomide moiety binds with high specificity to the CRBN E3 ubiquitin ligase, while the C8-COOH linker offers a reactive site for conjugation with ligands that target proteins of interest. When incorporated into a PROTAC molecule, this conjugate facilitates the induced proximity between the E3 ligase and the target protein. This triggers ubiquitination of the target protein, marking it for subsequent degradation by the 26S proteasome, thus providing a powerful strategy for selective and efficient protein knockdown.

Applications

Pomalidomide-C8-COOH is extensively used in both academic and industrial research settings for the development of next-generation PROTACs. Key applications include the design of custom protein degraders for validation of novel drug targets, generation of tool compounds for mechanistic biology studies, and preclinical evaluation of PROTAC efficacy in oncology, immunology, and neurodegenerative disease models. Its robust ability to recruit CRBN and support linker attachment makes it a preferred intermediate in high-throughput screening and structure-activity relationship (SAR) studies for targeted protein degradation therapies.