In recent years, there have been significant advances in drug development to identify and target disease-causing genetic mutations.¹ In order to achieve disease response, drugs commonly bind to a receptor or its ligand, inhibiting the pathway and its downstream protein production. In oncology, challenges arise once mutations occur or if a suitable binding site does not exist. As drug development evolves, emerging novel agents are eliminating these proteins directly rather than inhibiting them through the traditional binding site approach. These protein-eliminating therapies are taking advantage of the cellular machinery responsible for routine protein disposal. In 2026, two drug classes using this proteasome system were approved, transforming this concept into new options for patients: proteolysis targeting chimeras (PROTACs) and cereblon (CRBN) E3 ligase modulators (CELMoDs). 

First, a brief history: Lenalidomide (Revlimid) and thalidomide (Thalomid) were approved in 2006 by the Food and Drug Administration (FDA) for the treatment of multiple myeloma (MM), followed by pomalidomide (Pomalyst) in 2013.² They were classified as immunomodulatory imide drugs (IMiDs) whose mechanism of antineoplastic activity was poorly understood. Research into the cause of their teratogenicity³ led to the discovery that the interaction with CRBN,⁴ a component of the cell’s protein-disposal machinery, results in the degradation of developmental proteins and, consequently, the characteristic birth defects. This mechanism also explained the activity of this class in MM. In 2014, researchers found these agents enhanced degradation of Ikaros (IKZF1) and Aiolos (IKZF3) proteins, resulting in both reduced myeloma cell survival and increased immune response.^5,6 With the recent approval of iberdomide (Zenbexus),² the evolution of IMiDs for MM has led to the emergence of the cereblon E3 ligase modulator (CELMoD) class, a next-generation group of CRBN-targeting agents.⁷ Iberdomide’s greater affinity for CRBN enhances the mechanism described above and demonstrates efficacy in some patients, following progression on earlier IMiDs.  

In moving from hematologic malignancies to solid tumors, the new drug vepdegestrant (Veppanu)² is indicated for adults with estrogen receptor-1 (ESR1)-mutated advanced or metastatic breast cancer who have estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative disease and whose cancer has progressed on endocrine therapy. Vepdegestrant is a protein degrader that binds to the ER and E3 ligase CRBN to directly eliminate the ER protein. This mechanism has resulted in the PROTAC class.^8–10 

Each of these products is interesting in its own right, but even more compelling is the common thread linking the distinct drugs. Both agents exploit the ubiquitin-proteasome system (UPS), a cellular mechanism responsible for the removal of damaged proteins,¹¹ but they do so by interacting with CRBN in different ways. CELMoDs, also referred to as molecular glues, differ from conventional therapies in that they do not rely on a traditional target-receptor interaction. Instead, binding to CRBN promotes the formation of protein complexes that include substrates, such as IKZF1 and IKZF3, which are subsequently degraded by the UPS.⁶ Meanwhile, PROTACs bind to E3 ligases (e.g., CRBN) in a more familiar way, using a linker to connect them to the protein that is being overexpressed.¹² 

Using cellular cleanup machinery to reduce these proteins may not seem terribly different from inhibiting them, but the story is more nuanced. CRBN is, itself, one of many E3 ligase components that could be used to exploit the UPS, which is the real breakthrough from a drug-development standpoint. This protein-degradation mechanism can be used both to expand therapeutic options for existing targets and to provide treatments for cancers that lack typical binding sites and were previously considered to be “undruggable.”¹⁰ 

CELMoDs and PROTACs are new classes with a sole approval for each, but they represent a significant evolution in drug development. There are many promising agents in clinical development — including mezigdomide, another CELMoD,⁷ and various PROTACs¹³ — to treat cancers such as prostate, synovial sarcoma, T-cell lymphoma and chronic lymphocytic leukemia. This mechanism is being explored for nononcologic indications like autoimmune disorders as well. 

Managed care takeaway 

As the oncology landscape evolves, awareness of new drug-development pathways is important from both planning and preparedness perspectives. PROTACs are following a trajectory similar to bispecific T-cell engagers, where an initial proof of concept (e.g., blinatumomab [Blincyto]) established a mechanism that could later be applied across multiple therapeutic targets. PROTACs are using the E3 ligase UPS degradation system to eliminate target proteins, and this will be the beginning of another slew of new drug approvals. 

However, new and novel does not mean better. Coverage, formulary and utilization management decisions regarding each new agent will depend on the answers to several key questions: Does this new drug improve outcomes, address an unmet need or overcome resistance? Does it reduce treatment burden or provide incremental benefit compared with existing treatment options? Each of these new agents will need to be evaluated based on its clinical merit and in relationship to other available therapies.  

With the Accelerated Approval of many new oncology agents, data on the most meaningful outcomes, such as overall survival, as well as comparative data versus current standards of care, are often lacking. As a result, managed care stakeholders must work to discern which agents represent a meaningful step forward for patients and which simply offer another option in the therapeutic armamentarium.

All brand names are property of their respective owners. 
 

References 

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