A patent review of the ubiquitin ligase system: 2015–2018

ABSTRACT

Introduction: Ubiquitin-proteasome system (UPS) has been validated as a novel anticancer drug target in the past 20 years. The UPS contains two distinct steps: ubiquitination of a substrate protein by ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3), and substrate degradation by the 26S proteasome complex. The E3 enzyme is the central player in the ubiquitination step and has a wide range of specific substrates in cancer cells, offering great opportunities for discovery and development of selective drugs.

Areas covered: This review summarizes the recent advances in small molecule inhibitors of E1s, E2s, and E3s, with a focus on the latest patents (from 2015 to 2018) of E3 inhibitors and modulators.

Expert opinion: One strategy to overcome limitations of current 20S proteasome inhibitors is to discover inhibitors of the upstream key components of the UPS, such as E3 enzymes. E3s play important roles in cancer development and determine the specificity of substrate ubiquitination, offering novel target opportunities. E3 modulators could be developed by rational design, natural compound or library screening, old drug repurposes, and application of other novel technologies. Further understanding of mechanisms of E3–substrate interaction will be essential for discovering and developing next-generation E3 inhibitors as effective anticancer drugs.

KEYWORDS:

• E3
• protein ubiquitination and degradation
• ubiquitin-proteasome system
• cancer therapy
• drug discovery

Article highlights

• Protein ubiquitination is a crucial post-translational process that is involved in the development and progression of human cancers.

• E3 ligase is the central player in ubiquitination process and in the ubiquitin-proteasome system, and has a wide range of specific substrate proteins, suggesting it as a novel anticancer target.

• Discovery of E3 inhibitors has challenges in selectivity, given the complexity of E3 substrate proteins.

• Understanding the mechanism of action of E3 is critical for developing E3 inhibitors or modulators.

• Availability of novel technologies (e.g. phage display-based ubiquitin variant, AlphaScreen assay, using small molecules such as PROTACs/molecular glues, etc.) makes it feasible to screen and discover potent, specific E3 inhibitors.

This box summarizes key points contained in the article.

Acknowledgments

We thank Hassan Cheaito and Rania Fardous for critical reading of the manuscript. This work was partially supported by Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety Fund (No: 201605; to Xin Li), National Cancer Institute grant R21CA184788 (to QP Dou) and NIH grant P30 CA022453 (to the Karmanos Cancer Institute at Wayne State University) as well as Karmanos internal funds.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work is supported by Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety Fund (No: 201605; To: Dr. Xin Li), and by the National Natural Science Foundation of China (Grant No. 81772492/H1615), as well as by a National Cancer Institute grant R21CA184788 (to QP Dou) and a National Institutes of Health grant P30 CA022453 (to the Karmanos Cancer Institute at Wayne State University).