Ubiquitination, Biotech Startups, and the Future of TRIM Family Proteins: A TRIM-Endous Opportunity

Abstract

Ubiquitination is a post-translational modification that has pivotal roles in protein degradation and diversified cellular processes, and for more than two decades it has been a subject of interest in the biotech or biopharmaceutical industry. Tripartite motif (TRIM) family proteins are known to have proven E3 ubiquitin ligase activities and are involved in a multitude of cellular and physiological events and pathophysiological conditions ranging from cancers to rare genetic disorders. Although in recent years many kinds of E3 ubiquitin ligases have emerged as the preferred choices of big pharma and biotech startups in the context of protein degradation and disease biology, from a surface overview it appears that TRIM E3 ubiquitin ligases are not very well recognized yet in the realm of drug discovery. This article will review some of the blockbuster scientific discoveries and technological innovations from the world of ubiquitination and E3 ubiquitin ligases that have impacted the biopharma community, from biotech colossuses to startups, and will attempt to evaluate the future of TRIM family proteins in the province of E3 ubiquitin ligase-based drug discovery.

Keywords: E3 ligases; TRIM family; drug discovery; startups; ubiquitination.

Figure 1

Types of E3 ubiquitin ligases and the current landscape of biotech startups with their origin in E3 ubiquitin biology. Schematic representation of exemplary startups working with different approaches in the space of E3 ubiquitin drug discovery.

Figure 2

Major events in the history of PROTAC and UPS-based drug discovery and highlights of important PROTACS/E3 ubiquitin ligase-based drugs in the pipeline. (A) Timeline showing developments in the history of drug discovery in UPS with focus on PROTACs. (B) Important PROTACs/degrader drugs or inhibitors targeting E3 ligases that are currently in the clinical pipeline at the biotech startups that were founded in the second decade of E3 ubiquitin drug discovery (2011–2020). IND: investigational new drug.

Figure 3

NASDAQ Biotechnology Index (NBI) and S&P 500 stock exchange data on a logarithmic scale. As of January 2013, the NASDAQ Biotechnology Index (blue) has surpassed the S&P 500 stocks (red), maintaining record growth. Some of the historic events in the life sciences that have influenced the biotechnology industry have also been marked on the timeline. Data source: NASDAQ Biotechnology Index. Credit: Yahoo Finance.