PPARs and PROTACs: A new strategy in cancer therapeutics

Xia & He Publishing Inc.Sep 13 2024

The growing challenge in cancer therapy lies in overcoming tumor heterogeneity, drug resistance, and associated side effects. Peroxisome proliferator-activated receptors (PPARs) are pivotal regulators of metabolic processes, including fatty acid oxidation, glucose metabolism, and insulin sensitivity. Their role in cancer has garnered attention due to their potential as therapeutic targets. PPARs are categorized into three subtypes: PPARα, PPARβ/δ, and PPARγ. Each subtype plays distinct roles in cancer development and progression, with their activation or inhibition leading to varied therapeutic outcomes across different tumor types. This dual role complicates the development of PPAR-targeted therapies, necessitating a deeper understanding of their mechanisms in specific cancers.

The dual roles of PPARs in cancer treatment

PPARs exhibit a dualistic nature in cancer therapy, where their activation or inhibition can either suppress or promote tumor growth depending on the cancer type. For instance, PPARα is highly expressed in kidney chromophobe cancer and plays a significant role in liver cancer, where its agonists have shown contradictory effects. In gastrointestinal cancers, particularly colorectal cancer, PPARδ has been implicated in promoting tumorigenesis. PPARγ, the most studied subtype, exhibits a complex role in urologic cancers like bladder and prostate cancers, where it can act both as a tumor promoter and suppressor. This complexity necessitates a tailored approach in targeting PPARs for cancer treatment.

Proteolysis targeting chimeras (PROTACs) and their significance

PROTACs represent a novel and promising approach in cancer therapy. Unlike traditional inhibitors, PROTACs promote the degradation of target proteins through the ubiquitin-proteasome system, offering an "event-driven" mechanism that does not rely on binding affinity to the active site. This mechanism has shown significant potential in targeting various cancer-related pathways, including cell proliferation, apoptosis, and tumor immunity. The development of PROTACs targeting PPARs could enhance the specificity and efficacy of cancer therapies, particularly in cases where traditional PPAR-targeted therapies have shown limited success.

Feasibility and advantages of PPAR-targeting PROTACs

The design of PROTACs targeting PPARs presents a unique opportunity to overcome the challenges associated with PPAR-targeted cancer therapies. PROTACs offer enhanced tumor specificity due to the differential expression of E3 ligases in tumor cells compared to normal cells. This specificity could potentially reduce off-target effects and improve therapeutic outcomes. Additionally, the development of bifunctional molecules that bring PPAR-activating proteins closer together could enhance the activation effects beyond what is achievable with simple agonists. However, the absence of currently available PPAR-targeting PROTACs highlights the need for continued research and development in this area.

Challenges and future directions

Despite the promise of PPAR-targeting PROTACs, several challenges remain. The selection of appropriate PPAR subtypes and E3 ligases for PROTAC design is critical, as is the development of small molecules with high affinity for PPARs. Additionally, the structural heterogeneity of PPAR ligands complicates the development of universally applicable pharmacophores. Future research should focus on optimizing the molecular design of PROTACs, enhancing their tumor-targeting specificity, and developing novel heterobifunctional molecules that can effectively modulate PPAR activity in cancer.

Conclusions

PPAR-targeting PROTACs offer a promising new avenue for cancer treatment, particularly for tumors with complex metabolic profiles. By leveraging the advantages of targeted protein degradation, these compounds could potentially overcome the limitations of traditional PPAR-targeted therapies. However, their development will require careful consideration of the specific disease context and a commitment to overcoming the challenges associated with their design and implementation. With continued research and innovation, PPAR-targeting PROTACs could become a powerful tool in the fight against cancer.