Bringing Silicon to Drugs: Modular Construction of Sila-Pharmacophores for the Development of Target Protein Degraders
Zhigang Wu, Xujiang Zhu, Yueqiu Li, Xia Wang, Meizhen Huang, Zhenyuan Dong, Jiangnan Zheng, Ruijun Tian, Chuan He, and Jie Wang
Most cancer drugs work by blocking the activity of harmful proteins, but the proteins themselves remain inside the cell. This can limit how long treatments remain effective and may allow cancer cells to develop resistance over time. A newer approach, known as targeted protein degradation, aims to overcome this challenge by marking disease-causing proteins for destruction using the cell’s natural waste-disposal system. Because many diseases are driven by proteins that are difficult to target with conventional drugs, this strategy has emerged as a promising new frontier in biomedical science.
Researchers at Southern University of Science and Technology investigated whether replacing carbon with silicon in these molecules could improve the design of protein degraders. Silicon is widely used in electronics and materials science, but its potential in drug development remains relatively unexplored. If successful, silicon-based drug components could expand the range of medicines available to treat human disease.
To approach this, the team created a library of 64 silicon-containing protein degraders. To identify the most promising candidates, they tested the compounds in living cells using a HaloTag system, which allowed them to measure how effectively the molecules triggered the breakdown of a target protein while remaining stable enough to function.
The results revealed an unexpected finding. Neither larger molecules nor those that were more attracted to fats performed best. Instead, the three-dimensional arrangement of atoms around the silicon center had the greatest impact on activity. Several silicon-containing compounds outperformed similar carbon-based molecules, suggesting that silicon can influence how these degraders behave inside cells.
One compound, called SiD52, emerged as the most promising candidate. Researchers linked SiD52 to an existing cancer drug that targets the ALK protein, creating a degrader that not only recognized the protein but also directed it toward destruction. The resulting compound worked at very low concentrations and reduced tumour growth in mice when administered orally.
The approach was also successfully applied to other difficult targets, including CDK9 and EGFR, proteins that help drive the growth and survival of many cancers. While further testing will be needed before these compounds can be considered for human use, the study demonstrates how silicon chemistry may provide new tools for designing medicines capable of eliminating disease-causing proteins rather than simply blocking them. By expanding the toolkit available to drug developers, this work could help accelerate the discovery of future treatments for cancer and other diseases driven by difficult-to-target proteins.
