The Hu lab focus on Medicinal Chemistry and Chemical Biology research, we are dedicated to studying and regulating life processes through chemical means. Focusing on bifunctional molecules like PROTAC and PhosTAC, we are a biology-driven, chemistry-empowered research lab. We use chemical approaches to engineer life and control the onsets of diseases, aiming to become "engineers of life." Our goal is to develop treatment methods for diseases such as Alzheimer's and cancer based on bifunctional molecular drugs.
What are bifunctional molecules?
Bifunctional molecules typically consist of two small molecules with different functions: one end binds to a target protein (Warhead), while the other end often binds to an enzyme (such as E3 ligase, phosphatase, etc.). By inducing the proximity of the target protein and enzyme, they form a ternary complex, regulating the target protein through processes like degradation.
Figure 1: Composition of bifunctional molecules. Figure 2: Induction of ternary complex by bifunctional molecules.
PROTAC is the most representative bifunctional molecule, inducing the proximity of the target protein and E3 ligase, adding ubiquitin tags to the target protein. This leads to the recognition and degradation of the target protein by the proteasome, achieving thorough target inhibition and overcoming drug resistance. PROTAC has revolutionized drug development, becoming a trillion-dollar drug development direction.
Figure 3: PROTAC working principle.
What are the advantages of bifunctional molecules?
Bifunctional molecules have a unique event-driven mode. After driving one cycle, they can dissociate from the ternary complex, acting as catalysts. Additionally, the ternary complex provides higher selectivity due to induced protein-protein interactions. PROTAC, by degrading the target protein, can overcome some drug resistance caused by mutations in the target protein.
Protein phosphorylation is one of the most important protein regulation mechanisms in cells, influencing almost all life processes. Hu and collaborators developed a new generation of bifunctional molecules regulating protein phosphorylation - PhosTAC. PhosTAC has advantages like high efficiency and specificity, holding potential as a new tool for drug development. The significant research and therapeutic potential of PhosTAC and other bifunctional molecules are yet to be fully explored and developed.
Figure 4: PhosTAC working principle.
What are we aiming to achieve?
The laboratory focuses on using bifunctional molecules to regulate life processes. For example, using PhosTAC to precisely control protein function. The research directions of our project mainly include:
- Chemical biology exploration:
Exploring diverse protein modifications (e.g., ubiquitination, phosphorylation, glycosylation) with bifunctional molecules has immense potential. Post-translational modifications like glycosylation and phosphorylation play crucial roles in life processes and contribute to various diseases. Therefore, regulating these modifications with bifunctional molecules has significant scientific and pharmaceutical potential. The group concentrates on using bifunctional molecules to regulate post-translational modifications, exploring various ways to modulate protein functions. The focus is on discovering new methods to control disease-related proteins causing cancer, neurodegenerative diseases, etc.
Figure 5: Regulating Diverse Life Processes with BiFunctional Molecules.
- Drug Development:
The research group focuses on drug development using bifunctional molecules. By utilizing bifunctional molecules like PROTAC and PhosTAC to regulate protein over-phosphorylation, degrade pathogenic proteins, and explore novel therapeutic methods for various diseases. They aim to develop drugs for neurodegenerative diseases, cancer, and other conditions.
- Immunochemical Biology:
The human immune system is a crucial force in destroying cancer cells and maintaining overall health. However, excessive activation of the immune system can lead to inflammation, a significant cause of autoimmune diseases. Conditions like rheumatoid arthritis, caused by inflammatory factors, affect approximately 7.6% to 9.4% of people globally. Inflammation in the nervous system is confirmed as a significant driving factor in various neurodegenerative diseases.
This laboratory emphasizes using bifunctional molecules to regulate the immune system, exploring and developing various drugs:
a) Activating the immune system: Using bifunctional molecules to activate the immune system, promoting its ability to eliminate cancer cells. This approach is utilized for developing new antibodies and cell therapies.
b) Inhibiting excessive immune system activation: Developing novel treatment methods for autoimmune diseases by using bifunctional molecules to suppress overactive immune responses. Also, exploring the inhibition of neurological inflammation for developing new treatments for neurodegenerative diseases.
Figure 6: Activating the immune system with BiFunctional Molecules.
