What are Nrf2 degraders and how do they work?

Nuclear factor erythroid 2–related factor 2 (Nrf2) is a transcription factor that plays a critical role in cellular defense mechanisms. It regulates the expression of a wide array of genes involved in antioxidant responses, detoxification processes, and overall cellular homeostasis. While the activation of Nrf2 has been extensively studied for its protective roles, recent research has turned its focus to Nrf2 degraders. These novel compounds are designed to inhibit Nrf2 activity by promoting its degradation, offering new therapeutic avenues for diseases where Nrf2 is aberrantly active.

Nrf2 is normally held in check by its inhibitor, Kelch-like ECH-associated protein 1 (Keap1), which targets Nrf2 for ubiquitination and subsequent proteasomal degradation. Under oxidative stress, Nrf2 is released from Keap1, translocates to the nucleus, and activates the expression of genes that mitigate cellular damage. However, in certain pathological conditions, such as cancer, Nrf2 is constitutively activated, leading to an adaptive resistance to chemotherapeutic agents and promoting tumor survival.

Nrf2 degraders are small molecules designed to enhance the interaction between Nrf2 and Keap1, thereby promoting the ubiquitination and degradation of Nrf2 even under conditions where it would normally be stabilized. By accelerating the degradation process, these degraders effectively reduce the levels of Nrf2, thereby diminishing its activity. This can be achieved through various mechanisms, such as enhancing the affinity of Keap1 for Nrf2 or by stabilizing the Keap1-Nrf2 complex.

The development of Nrf2 degraders involves high-throughput screening of small molecule libraries to identify candidates that can promote the degradation of Nrf2. Once potential compounds are identified, they undergo rigorous testing to evaluate their efficacy and specificity. The goal is to develop degraders that can selectively target Nrf2 without interfering with other cellular processes.

The therapeutic potential of Nrf2 degraders is significant, particularly in the field of oncology. In many cancers, constitutive activation of Nrf2 leads to enhanced survival of cancer cells, resistance to chemotherapy, and poor prognosis. By degrading Nrf2, these compounds can potentially sensitize cancer cells to chemotherapeutic agents, making them more susceptible to treatment. This can enhance the efficacy of existing cancer therapies and possibly reduce the required dosage, thereby minimizing side effects.

Beyond cancer, Nrf2 degraders may have applications in other diseases characterized by aberrant Nrf2 activity. For instance, Nrf2 is implicated in the pathogenesis of several neurodegenerative diseases, where its dysregulation contributes to disease progression. By modulating Nrf2 levels, degraders could offer a new approach to managing these conditions.

Moreover, Nrf2 degraders could play a role in metabolic diseases. For example, in conditions like non-alcoholic fatty liver disease (NAFLD), excessive activation of Nrf2 has been linked to disease progression. Targeting Nrf2 with degraders could potentially ameliorate the pathological features of NAFLD and improve clinical outcomes.

However, the development of Nrf2 degraders is not without challenges. One major concern is the potential for off-target effects, given the broad role of Nrf2 in cellular homeostasis. Selectivity is paramount to ensure that degradation of Nrf2 does not adversely affect normal cellular functions. Additionally, long-term studies are required to assess the safety and efficacy of these compounds in clinical settings.

In conclusion, Nrf2 degraders represent a promising new class of therapeutic agents with the potential to address a variety of diseases where Nrf2 is pathologically active. While still in the early stages of development, these compounds could revolutionize the treatment landscape for conditions ranging from cancer to neurodegenerative and metabolic diseases. As research progresses, it will be crucial to refine these degraders to maximize their therapeutic benefits while minimizing potential risks.