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.
Highlights
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
PROteolysis TArgeting Chimeras (PROTACs) are bifunctional, two-headed, small molecules connected by an optimal linker, having one head that selectively binds a target protein and a second head that binds to an E3 ubiquitin ligase, and brings the E3 ligase into the proximity of a specific disease-causing target protein so that it can be tagged with ubiquitin and subsequently degraded by the 26S proteasome
We can say that E3 ubiquitin ligase-based drug discovery research is moving towards a promising future in its third decade (2021–2030), and its sphere of influence is progressively growing due to its collaborative business model with big pharma and backing from biotechnology focused venture capital firms at different stages of investment
Summary
Thebiotechnology biotechnology and industries havehave grown rapidly over theover pastthe past decade. The scenario changed, in the second decade of E3 ubiquitin drug discovery ligase family. The scenario changed, in the second decade of E3 ubiquitin drug discovery (2011–2020), due to the development of many novel technologies, the growing interest that biotechnology-focused venture capital (VC) firms showed in backing innova-. (2011–2020), due to the development of many novel technologies, the growing interest that biotechnology-focused venture capital (VC) firms showed in backing innovative startups working in E3 ubiquitin drug discovery, and the progress made in our biological understanding of many E3 ligases. Following two successful IPOs of E3 ubiquitin drug discovery startups, Arvinas in 2018 [21] and C4 Therapeutics in 2020 [22], it is widely believed that targeting the ubiquitin-proteasome pathway is revolutionary, and possess the same market growth potential that kinase inhibitors once exhibited in the coming decade, i.e., the third decade of E3 ubiquitin drug discovery (2021–2030)
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