Towards new drug therapies by a better understanding of ubiquitin metalloprotease activity

Metallodubi - tools to study ubiquitin metalloprotease activity

The decoration of proteins with the small protein ubiquitin is one of the major processes by which Nature controls almost all cellular processes. This process of ubiquitination is regulated by nearly hundred different ubiquitin proteases in the human genome by removal of ubiquitin from its targets. An important family of ubiquitin proteases are the so called zinc-dependent metalloproteases. Because these ubiquitin metalloproteases regulate protein degradation, epigenetics and DNA repair, they have potential as drug targets. In this project, The Netherlands Cancer Institute and UbiQ Bio B.V. (short name UbiQ) form a highly complementary public-private partnership by combining expertise in protease research and ubiquitin research tool development.

In recent years it has become clear that the (mal)function of ubiquitin metalloproteases is linked to various diseases. For example, the expression of the ubiquitin metalloprotease MYSM1 is associated with tumor progression in colorectal cancer, making it a potential biomarker for clinical prognosis. The abnormal expression of the ubiquitin metalloprotease BRCC36 is associated with breast and nasopharyngeal carcinomas, making BRCC36 (activity) a promising prognostic marker and potential target in the therapies for these cancer types. An exciting finding is that ubiquitin metalloproteases also regulate T cell biology and thus might be of importance in immunotherapy development. Thus, the study and identification of ubiquitin metalloproteases holds potential for future (onco)therapy development.

However, to date there has been a lack of dedicated research tools for ubiquitin metalloproteases. The main reason for this is the difficulty in designing molecules that target the zinc-dependent active site of these proteases in an efficient manner. By using cutting-edge chemical synthesis technologies and advanced protease studies, this consortium will validate and improve recent developed research tools targeted specifically at ubiquitin metalloproteases. Besides mechanistic studies they will also investigate the potential of our tools for creating inhibitors of ubiquitin metalloproteases and identifying new ubiquitin metalloproteases.

Ultimately, this consortium will develop highly desired research tools for the scientific community which can also form a basis for future drug development aimed at ubiquitin metalloproteases.

Ubiquitin metalloproteases are important regulators of protein homeostasis and their malfunction is linked to various diseases. In this project they will develop unique reagents that will help to study these proteases and as such aid in developing potential therapies aimed at interfering with their activity.
Technology Readiness Level (TRL)
3 - 4
Time period
36 months