Enhancing the Effectiveness of PROTAC: A Groundbreaking Study

The use of small molecule degraders, such as PROTACs (PROteolysis TArgeting Chimeras), represents a novel therapeutic strategy by inducing the rapid degradation of disease-causing proteins. This approach offers a promising new direction for the treatment of various diseases, including cancer.

A significant advancement in this field was recently published in the journal Nature Communications on July 2nd. The study, led by a team of researchers, identified several cellular signaling pathways that regulate the targeted degradation of key proteins such as BRD4, BRD2/3, and CDK9 using PROTACs.

To determine how these intrinsic pathways affect protein degradation, the researchers screened for changes in BRD4 degradation in the presence or absence of MZ1, a CRL2VHL-based BRD4 PROTAC. The findings indicated that various intrinsic cellular pathways might spontaneously inhibit BRD4-targeted degradation, which can be counteracted by specific inhibitors.

Key Findings: The researchers validated several compounds as degradation enhancers, including PDD00017273 (a PARG inhibitor), GSK2606414 (a PERK inhibitor), and luminespib (an HSP90 inhibitor). These results demonstrate that multiple intrinsic cellular pathways impact the effectiveness of protein degradation at different steps.

In HeLa cells, it was observed that PARG inhibition by PDD could significantly enhance the targeted degradation of BRD4 and BRD2/3 but not of MEK1/2 or ERα. Further analysis revealed that PARG inhibition promotes the formation of the BRD4-MZ1-CRL2VHL ternary complex and K29/K48-linked ubiquitination, thereby facilitating the degradation process. Additionally, HSP90 inhibition was found to enhance BRD4 degradation post-ubiquitination.

Mechanistic Insights: The study explored the mechanisms underlying these effects, revealing that PERK and HSP90 inhibitors are primary pathways influencing protein degradation via the ubiquitin-proteasome system. These inhibitors modulate different steps in the degradation process induced by chemical compounds.

Moreover, the researchers investigated whether PROTAC enhancers could boost the efficiency of potent degraders. SIM1, a recently developed trivalent PROTAC, was shown to more effectively induce the formation of the BRD-PROTAC-CRL2VHL complex and subsequent degradation of BRD4 and BRD2/3. Combining SIM1 with PDD or GSK resulted in more efficient cell death than using SIM1 alone.

The study also found that PARG inhibition could effectively degrade not only the BRD family proteins but also CDK9, suggesting a broader applicability of these findings.

Future Implications: The authors of the study anticipate that further screenings will identify additional cellular pathways that contribute to the understanding of targeted protein degradation mechanisms. These insights could lead to the development of more effective therapeutic strategies for a range of diseases.

Reference: Yuki Mori et al. Intrinsic signaling pathways modulate targeted protein degradation. Nature Communications (2024).  the full article https://www.nature.com/articles/s41467-024-49519-z

This breakthrough study underscores the potential of PROTACs in therapeutic applications and highlights the importance of understanding cellular signaling pathways to enhance the effectiveness of targeted protein degradation.