Researchers at the Baylor College of Medicine have developed a computational workflow combining artificial intelligence and high-throughput proteomics to accelerate the discovery of molecular glues. The study introduces compounds designed to eliminate VAV1, an immune-cell signaling protein implicated in blood cancers and autoimmune disorders.
Targeting Immune Proteins by Elimination Rather Than Inhibition
Traditional drug design usually focuses on inhibiting the function of a disease-linked protein. Scientists at Baylor College of Medicine are taking a different route by aiming to remove the protein entirely. Many scientists are increasingly exploring a new way to treat disease: instead of blocking harmful proteins, they aim at eliminating them entirely. One promising approach uses molecular glues, which act like matchmakers inside cells,
said Dr. Jin Wang, director of the Center for NextGen Therapeutics and professor in pharmacology and biochemistry.
These small molecules bring the target protein into contact with the cell’s natural waste disposal machinery, marking it for destruction. Wang’s team focused specifically on VAV1, a protein found predominantly in immune cells that regulates T-cell activation. While normal VAV1 activity is essential for immune function, abnormal signaling drives conditions such as T-cell lymphomas and chronic inflammatory disorders. Eliminating the entire protein offers a potentially more complete therapeutic effect than simply inhibiting one of its functions.
Screening Molecular Libraries and Verifying Cellular Pathways
To identify compounds capable of degrading VAV1, researchers screened an extensive molecule library using high-throughput proteomics, a technology capable of assessing thousands of proteins simultaneously. This unbiased screening identified a series of active compounds, including one designated as NGT-201-12.
To find compounds capable of degrading VAV1, we screened a library of molecules using high-throughput proteomics, a technology that can assess thousands of proteins simultaneously.
Dr. Hanfeng Lin, postdoc in the Wang lab
Follow-up experiments confirmed that these compounds operate through the cell’s natural protein-recycling apparatus. Specifically, the degradation process relies on cereblon, or CRBN, which serves as a vital component of the protein-degradation pathway within human cells.
GluePlex Workflow and the Discovery of a New Degron
A persistent hurdle in molecular glue research is determining how these compounds recruit their specific targets. To overcome this, the Baylor-led team engineered a computational workflow called GluePlex, which merges artificial intelligence, protein-structure prediction tools, and physics-based modeling. GluePlex successfully predicted how VAV1, cereblon, and the molecular glue assemble into a stable three-part complex without relying on any prior experimental structure of the complex.
The model identified a specific region of VAV1, known as the SH3-2 domain, as being essential for degradation. Experimental tests confirmed the prediction and pinpointed the exact spot the glue uses: a small surface loop on VAV1 that acts as a degradation signal, or ‘degron.
Dr. Hanfeng Lin, postdoc in the Wang lab
Until recently, most known cereblon-dependent molecular glues were believed to require a specific structural motif known as a G-loop. The discovery that cereblon can recognize an entirely different structural feature broadens the range of proteins that might be targeted for degradation in future therapies.
Medicinal Chemistry Optimization and Patent Filings
Following the identification of the initial binding mechanism, the team turned to medicinal chemistry to enhance the compounds. By introducing chlorine atoms into the molecular structure, the researchers reduced molecular flexibility and increased overall degradation efficiency. This optimization yielded NGT-201-18, a compound that demonstrated substantially improved potency and formed a stronger degradation complex.
When tested in primary human T cells, NGT-201-18 successfully reduced VAV1 levels and suppressed T-cell activation. Dose-response proteomics identified VAV1 as the principal target while also revealing the degradation of an off-target protein, LIMD1, which carries a canonical G-loop degron. These findings emphasize the necessity of proteome-wide profiling when evaluating novel therapeutics.
Commercial and intellectual property efforts are moving alongside the academic publication in Nature Communications. Baylor College of Medicine filed a provisional patent application in the United States covering the VAV1 molecular glue degrader compounds in the NGT-201 series and methods for their use.