Molecular Glues as a New Modality: Case Studies in Cereblon-Based Degraders for Hematologic Cancers

Molecular Glues as a New Modality: Case Studies in Cereblon-Based Degraders for Hematologic Cancers

Molecular glues represent an emerging class of therapeutic agents. These small molecules stabilize interactions between proteins. In doing so, they often trigger the degradation of disease-relevant targets. Unlike traditional inhibitors, molecular glues do not simply block protein function. Instead, they promote the removal of the target protein from the cell.

Cereblon-based degraders form the most advanced group of molecular glues in clinical use. Cereblon acts as a substrate receptor within the CRL4 E3 ubiquitin ligase complex. Certain drugs bind to cereblon and create a new surface. This surface then recruits specific proteins, known as neosubstrates, for ubiquitination and subsequent degradation.

Immunomodulatory drugs provided the first major clinical success. Lenalidomide and pomalidomide bind cereblon and induce degradation of transcription factors IKZF1 and IKZF3. These proteins play critical roles in multiple myeloma and certain lymphomas. As a result, the drugs produce strong anti-myeloma activity. They also stimulate immune responses that further support their therapeutic effect.

Newer cereblon modulators improve on these earlier agents. Iberdomide and mezigdomide show higher potency and more selective degradation profiles. Clinical studies demonstrate deeper responses in relapsed or refractory multiple myeloma. Moreover, these compounds retain activity in some patients who previously progressed on lenalidomide or pomalidomide.

Researchers continue to expand the range of neosubstrates. Different molecular glues can redirect cereblon toward distinct proteins. This flexibility allows targeting of additional drivers in hematologic cancers. In addition, the approach works against proteins that lack traditional binding pockets for inhibitors.

Challenges still remain. Resistance can emerge through mutations in cereblon or alterations in downstream pathways. Tissue-specific expression of neosubstrates may also limit broader application. Furthermore, prolonged degradation of certain targets can produce unwanted effects on normal immune function.

Despite these limitations, cereblon-based molecular glues have already changed treatment standards in multiple myeloma. Ongoing case studies continue to refine dosing, combination strategies, and patient selection. These efforts strengthen the position of molecular glues as a distinct and valuable modality in oncology.