Molecular targeting of E3 ligases – a therapeutic approach for cancer

Abstract

Background : The ubiquitin-proteasomal degradation pathway plays a critical role in protein degradation and regulates a wide variety of cellular functions. This highly conserved post-translational modification of proteolytic processes is mainly carried out by substrate-specific E3 ligases. The deregulation of E3 ligases contributes to cancer development and their overexpression is often associated with poor prognosis. Objectives : We review the current understanding of E3 ligases, their functional role in cancer pathogenesis, current progress and development of certain ubiquitin E3 ligases as targets for therapeutic intervention. Methods : Preclinical and clinical data for E3 ligase inhibitors available in the public domain are discussed. Conclusions : With the growing understanding of their role in cancer development and progression, E3 ligases have emerged as potential anticancer targets for therapeutic intervention.

Regulation of SMN Protein Stability

“…Conversely, protein-protein interactions may sterically hinder access to or recognition of a targeting motif. Increased understanding of the processes and identification of the key regulatory proteins involved in the degradation of SMN could lead to the development of specific antagonists of these molecules (18). Nonetheless, we cannot rule out the possibility that other degradative enzymes may also play a role in SMN turnover.…”

Siah: A Promising Anticancer Target

“…Most proteins are targeted for degradation by polyubiquitination mediated by E3 ubiquitin ligases (1,2). The proteasome inhibitor, bortezomib, is used as a single agent or in combination with conventional therapies in the treatment of multiple myeloma and shows clinical efficacy as a novel anticancer drug.…”

“…The proteasome inhibitor, bortezomib, is used as a single agent or in combination with conventional therapies in the treatment of multiple myeloma and shows clinical efficacy as a novel anticancer drug. However, bortezomib blocks all protein proteolysis by the proteasome without discrimination, causing various systemic toxicities and the development of resistance (1). Treatment with bortezomib shows little to no efficacy against solid tumors and is limited to hematologic malignancies (1).…”

“…However, bortezomib blocks all protein proteolysis by the proteasome without discrimination, causing various systemic toxicities and the development of resistance (1). Treatment with bortezomib shows little to no efficacy against solid tumors and is limited to hematologic malignancies (1). E3 ubiquitin ligases are therefore a more specific and effective target for drug development in comparison with general proteasome inhibitors to reduce treatment side effects and increase efficacies (1).…”

“…Treatment with bortezomib shows little to no efficacy against solid tumors and is limited to hematologic malignancies (1). E3 ubiquitin ligases are therefore a more specific and effective target for drug development in comparison with general proteasome inhibitors to reduce treatment side effects and increase efficacies (1).…”