New Cereblon Binding Site Discovery Could Revolutionize Cancer Drug Development

A protein crucial to the function of many cancer drugs, cereblon, has revealed a hidden complexity that could lead to more effective and targeted therapies. Researchers have identified a previously unknown binding site on cereblon, offering new avenues for manipulating its activity and improving the precision of protein degradation-based drugs.

Cereblon: From Thalidomide’s Dark Past to Cancer Treatment

Cereblon initially gained notoriety as the target of thalidomide, a drug prescribed in the 1950s and 60s that tragically caused severe birth defects. However, decades later, thalidomide and related compounds were repurposed as treatments for blood cancers due to their ability to redirect cereblon to tag disease-causing proteins for destruction. This approach, known as targeted protein degradation, has become a promising area of cancer research.

Unveiling the Allosteric Site

Until recently, research focused on cereblon’s primary binding site – the same site utilized by thalidomide. A new study, published in Nature, marks the first identification and mapping of an allosteric site, a hidden binding pocket, on cereblon. This discovery, led by Christina Woo, professor of chemistry and chemical biology at Harvard University, in collaboration with scientists at GSK and Scripps Research Institute, opens up new possibilities for drug development.

How the Allosteric Site Changes Cereblon’s Function

The allosteric site doesn’t replace the main binding site but alters cereblon’s behavior once engaged. Researchers found that activating this second pocket can either enhance or inhibit the degradation of target proteins, depending on the existing drug bound to the primary site. This selectivity is a key aspect of the discovery. Scientists at GSK initially identified a small molecule, SB‑405483, that indicated the presence of this additional binding site.

Structural Insights into Cereblon’s Mechanics

Using cryo-electron microscopy, researchers visualized how cereblon changes shape when both binding sites are occupied. The structures revealed a previously unseen intermediate form and a more closed conformation, enhancing the protein’s ability to mark proteins for destruction. The allosteric ligand also subtly shifts the position of drugs binding to the main site, explaining the observed changes in protein degradation patterns.

Implications for Cancer Drug Development

The discovery of the allosteric site has several potential applications:

• Enhanced Drug Efficacy: Allosteric ligands could be used to boost the effectiveness of existing cereblon-based cancer drugs.
• Reduced Side Effects: By limiting the degradation of non-target proteins, allosteric ligands could minimize unwanted side effects.
• Novel Drug Design: The allosteric pocket itself could be targeted with new molecular glues or two-headed degrader molecules.

Understanding Natural Cereblon Regulation

Beyond drug development, this research suggests that cells may naturally regulate cereblon and related enzymes through similar mechanisms. Woo hypothesizes that endogenous small molecules may already be performing these regulatory functions, and further research is needed to understand these processes.

Cereblon and Protein Degradation: A Deeper Dive

Cereblon functions as part of a protein complex that tags other proteins for destruction. The process of targeted protein degradation involves designing small molecules that bring unwanted proteins to cereblon, initiating their disposal by the cell’s machinery. Recent research has also shown that C-terminal cyclic imides, post-translational modifications, act as physiological degrons on substrates for cereblon, influencing which proteins are targeted for degradation.