Pro(teasome targeting)-PROTACs: Advancing Targeted Protein Degradation with a Proteasome Binder Approach

• Applicant: Dr. Xinlai Cheng
• Subject Area: Pharmacy ; Biochemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 554469605

Our project introduces a groundbreaking approach in the field of targeted protein degradation (TPD), unveiling Proteasome targeting PROTACs (Pro-PROTACs) as an innovative strategy to overcome the limitations of traditional PROTAC technologies. By employing small molecule proteasome binders, Pro-PROTACs aim to navigate around the challenges posed by the limited availability of E3 ligase binders and the resistance mechanisms stemming from the absence of lysine residues for ubiquitination. This methodology capitalizes on the ubiquitous presence and essential function of the proteasome across various cell types, including cancer cells, offering a more flexible and potentially effective method for targeted degradation. Embracing TPD as a therapeutic strategy represents a significant paradigm shift in drug development, enabling the engagement of previously "undruggable" proteins. Our pioneering work with an innovative indirubin derivative has showcased its distinctive ability to directly bind the proteasome and facilitate BRD4 and CDK6 degradation in conjunction with JQ1 and Palbociclib, respectively. This advancement not only broadens the scope of TPD but also prompts further exploration into the complex mechanisms of action and the development of a versatile therapeutic platform. The project is delineated into two primary objectives: 1) Elucidating the Mechanism of Action: This objective focuses on mapping the detailed interactions between our compounds and the proteasome using advanced analytical techniques, identifying specific binding sites, and unraveling the precise mechanism of action. 2) Developing and Refining Pro-PROTACs: Here, our efforts concentrate on screening compounds, including indirubin derivatives, to discover those with enhanced binding affinity and degradation efficacy. We are committed to developing a new generation of Pro-PROTACs targeting a broad spectrum of proteins, such as ALK, to evaluate their activity and function in vitro and in cancer cells. This project transcends mere scientific exploration, aiming to forge new paths in drug design and therapeutic intervention. By advancing the development of Pro-PROTACs, our research endeavors to enrich therapeutic options for complex diseases like cancer. The implications of our work extend beyond scientific advancement, promising to introduce new therapeutic strategies, address critical clinical needs, and yield significant societal benefits. Through comprehensive analysis and development of ubiquitin-independent, proteasome-mediated protein degradation mechanisms and Pro-PROTACs, our project is poised to contribute significantly to molecular biology and drug discovery, heralding a new era in disease treatment.

• DFG Programme: Research Grants