What are EZH2 degraders and how do they work?

The field of oncology has witnessed remarkable advancements over the past few decades, with innovative therapies continuously emerging to tackle various forms of cancer. Among these groundbreaking developments is the introduction of EZH2 degraders. These novel therapeutic agents have generated significant interest within the scientific community for their potential to target and degrade a key protein implicated in cancer progression. In this blog post, we will delve into what EZH2 degraders are, how they function, and their current and potential applications in cancer treatment.

EZH2, or Enhancer of Zeste Homolog 2, is a protein that plays a pivotal role in the regulation of gene expression. It is a part of the Polycomb Repressive Complex 2 (PRC2), which functions by adding methyl groups to histone H3 on lysine 27 (H3K27me3), a modification that leads to the repression of gene transcription. While EZH2 is crucial for normal cellular functions, its dysregulation has been linked to the development and progression of various cancers, including lymphomas, sarcomas, and solid tumors. Overexpression or mutations in the EZH2 gene can lead to aberrant methylation patterns, resulting in the silencing of tumor suppressor genes and the promotion of oncogenic pathways.

EZH2 degraders are small molecules designed to selectively destabilize and degrade the EZH2 protein. Unlike traditional inhibitors that merely block the activity of a protein, degraders aim to eliminate the protein from the cell entirely. These degraders typically work through a mechanism known as proteolysis-targeting chimeras (PROTACs). A PROTAC molecule consists of two functional parts: one that binds to the target protein (in this case, EZH2) and another that recruits an E3 ubiquitin ligase. The E3 ligase tags the target protein with ubiquitin molecules, marking it for destruction by the proteasome, the cell’s degradation machinery.

This approach offers several advantages over traditional inhibition. Firstly, by completely degrading the protein, there is a reduced likelihood of the target protein reactivating, which can occur with reversible inhibitors. Secondly, degraders can potentially overcome resistance mechanisms that typically emerge with conventional therapies, as the target protein is eliminated rather than merely inhibited. Finally, since PROTACs function catalytically, they can act at lower doses compared to traditional inhibitors, potentially reducing off-target effects and improving patient safety profiles.

EZH2 degraders are primarily being developed and investigated for their potential in cancer treatment. Given the role of EZH2 in gene silencing and tumor progression, targeting this protein offers a promising therapeutic strategy for malignancies characterized by EZH2 dysregulation. One of the major types of cancer where EZH2 degraders are showing potential is in B-cell lymphomas. Specific mutations in EZH2 that lead to its hyperactivity have been identified in a subset of these lymphomas, making them excellent candidates for degrader therapy.

In addition to lymphomas, EZH2 degraders are being explored for their efficacy in treating various solid tumors, including prostate, breast, and ovarian cancers. Preclinical studies have demonstrated that EZH2 degradation can inhibit tumor growth and induce cancer cell death in models of these malignancies, suggesting a broad applicability of this therapeutic approach.

Furthermore, there is ongoing research into the potential use of EZH2 degraders in combination with other therapies. Combining degraders with immune checkpoint inhibitors, for example, could enhance anti-tumor immune responses, offering a synergistic approach to cancer treatment. Similarly, combining degraders with traditional chemotherapy or targeted therapies may overcome resistance mechanisms and improve overall treatment efficacy.

In conclusion, EZH2 degraders represent a promising new frontier in cancer therapy. By harnessing the power of targeted protein degradation, these agents offer a novel and potentially more effective approach to disrupting the oncogenic functions of EZH2. As research progresses, we can expect to see a growing body of evidence supporting the use of EZH2 degraders in clinical settings, bringing hope to patients with cancers driven by EZH2 dysregulation.