In our game, we show the functioning of the ubiquitin-proteasome system (UPS). It involves a cascade of enzymes that includes E1, the ubiquitin-activating enzyme; E2, the ubiquitin-conjugating enzyme; and E3, the ubiquitin ligase, which work together to attach ubiquitin to the target protein. This process, called ubiquitination, results in proteins being recognized and then degraded by the proteasome. The proteasome acts as a cellular recycling center, breaking down ubiquitin-tagged proteins into short amino acid chains that can be reused by the cell to, for example, synthesize new proteins.

The UPS plays an important role in maintaining protein homeostasis by controlling protein levels and eliminating those that are unwanted. In this way, it regulates various molecular processes, such as the cell cycle, signal transduction, and DNA repair. Mutations of UPS components can lead to protein accumulation, disrupt cellular functions, and contribute to the development of various diseases, including cancer, Alzheimer’s disease, and Parkinson’s disease.

What if we could harness our ubiquitin-proteasome system and tailor it to remove toxic disease-causing proteins? Well, this is no longer science fiction – it is how modern targeted protein degradation (TPD) therapies work. The strategy is simple; scientists design compounds that allow E3 ligases to bind proteins that they don’t normally recognize. The E3 ligases then bring them to E2 enzymes, resulting in ubiquitination of the proteins and degradation by the proteasome.

The two main classes of compounds using targeted protein degradation mechanisms are molecular glues and PROTACs. Molecular glues are small molecules that enhance interactions between an E3 ligase and a selected protein, while PROteolysis TArgeting Chimera (PROTAC) compound consist of two parts – one recognizes a specific E3 ligase, and the other recognizes the selected target protein.

Molecular glues, for example, lenalidomide or pomalidomide, have already achieved clinical success and are used to treat cancers such as multiple myeloma. Several PROTAC compounds are currently in advanced clinical trials against breast or prostate cancers, among others. TPD methods make it possible to destroy disease-causing proteins, including oncogenic proteins, and hold great promise for a wide range of therapeutic applications.

Our game was created with a primary focus on education, as we believe there’s no better way to learn than through having fun. To enrich the journey into the fascinating world of protein degradation, we have prepared a range of downloadable materials to enhance the learning experience and complement the knowledge gained from our game.