The role of E3 ubiquitin ligase in multiple myeloma: potential for cereblon E3 ligase modulators in the treatment of relapsed/refractory disease

by Selleckchem | Sep 13 2023

Introduction: Insights into the mechanisms of protein homeostasis and proteasomal degradation have led to new strategies of redirecting the ubiquitin-proteasome system (UPS) to reduce or eliminate proteins or survival factors key to malignant pathobiology, multiple myeloma (MM) in particular. These strategies have enabled researchers to target proteins that were previously considered difficult to modulate by pharmacological means.

Areas covered: This review provides a brief overview of UPS biology, particularly the role of the CRL4CRBN E3 ubiquitin ligase complex, and summarizes current strategies for co-opting the UPS, including CELMoD compounds, SNIPERs, PROTACs, and degronimids. A detailed discussion is provided on lead CELMoD compounds iberdomide and mezigdomide, which are currently being evaluated in clinical trials in patients with MM.

Expert opinion: Since a high proportion of patients develop drug resistance, it is vital to have novel therapeutic agents for treating relapsed patients with MM more effectively. It is encouraging that the expanding pathophysiological insight into cellular signaling pathways in MM increasingly translates into the development of novel therapeutic agents such as targeted protein degraders. This holds promise for improving outcomes in MM and beyond.

Comments:

The field of protein homeostasis and proteasomal degradation has provided valuable insights into the mechanisms underlying various diseases, including multiple myeloma (MM). The ubiquitin-proteasome system (UPS) is a crucial cellular pathway responsible for regulating protein levels and maintaining cellular balance. Researchers have made significant progress in understanding the UPS and have developed strategies to manipulate this system to target disease-causing proteins.

One key player in UPS biology is the CRL4CRBN E3 ubiquitin ligase complex. This complex plays a crucial role in the degradation of specific proteins by marking them with ubiquitin molecules, leading to their recognition and subsequent degradation by the proteasome. By targeting the CRL4CRBN complex, researchers have been able to modulate the degradation of proteins that were previously challenging to influence using traditional pharmacological approaches.

Several strategies have emerged for harnessing the UPS to target disease-related proteins. These include CELMoD compounds, SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers), PROTACs (Proteolysis-Targeting Chimeras), and degronimids. CELMoD compounds, such as iberdomide and mezigdomide, are particularly promising and have shown efficacy in preclinical and early clinical trials for MM.

Multiple myeloma is a complex disease characterized by the proliferation of abnormal plasma cells in the bone marrow. Unfortunately, a significant proportion of patients develop drug resistance over time, emphasizing the need for novel therapeutic agents. Targeted protein degraders, like CELMoD compounds, offer a potential solution by directly influencing the degradation of disease-causing proteins. The ongoing clinical trials evaluating iberdomide and mezigdomide in MM patients demonstrate the translational potential of these compounds.

The evolving understanding of the molecular pathways underlying MM and other diseases opens up exciting possibilities for the development of novel therapeutic agents. Targeted protein degraders, by redirecting the UPS, hold promise for improving treatment outcomes in MM and potentially other diseases as well. Continued research in this field is crucial to further refine and expand the repertoire of strategies that exploit the UPS for therapeutic benefit.