CRL4/CRBN Targeted Protein Degradation Complex Antibody Sampler Kit

Background

Targeted protein degradation is an experimental method of drug-based protein targeting that leverages endogenous proteolysis machinery, such as the the ubiquitin proteasome system (UPS), to selectively degrade proteins of interest (POIs). It is being actively explored as a therapeutic strategy to target and degrade POIs that contribute to disease progression (1). This approach differs from traditional small-molecule therapeutics that seek to suppress disease proteins (e.g., kinases) by sterically blocking catalytic domains. Proteolysis-targeting chimeras (PROTACs) and "molecular glue" degraders are the two primary degrader modalities used in UPS-mediated targeted protein degradation. PROTACs are bivalent, chemically-linked ligands that induce proximity between a POI and an E3 ubiquitin ligase, resulting in ubiquitination of the target protein, and its subsequent degradation by the UPS (2,3). Molecular glues are molecules that chemically generate novel interaction surfaces between two proteins, which can used to induce proximity between a POI and an E3 ligase. Cereblon (CRBN) is the substrate-recognition component of a Cullin-RING-ubiquitin (E3) ligase complex (CRL4/CRBN) that was among the first to be recognized for its therapeutic potential via targeted protein degradation (4). The CRL4/CRBN complex is comprised of CRBN, DDB-1, RBX1, and the scaffold protein CUL4A; its ligase activity is dynamically regulated via the covalent modification (neddylation) of CUL4A by NEDD8 (5). In unrelated mechanistic studies of multiple myeloma drugs, it was revealed that phthalimides (e.g., thalidomide, lenalidomide) promoted CRBN-dependent recruitment, ubiquitination, and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) (6). The discovery that phthalimides were functioning as molecular glue degraders that could selective degrade what were previously considered "undruggable" targets, led to a rapid acceleration and expansion of research into targeted protein degradation, with the promise of novel therapies for diseases deemed largely intractable using conventional small-molecule therapies (7-9).