Researchers at Scripps Research have developed a new approach to drug discovery that could be useful for targeting challenging proteins in the human body. This method, known as paralog hopping, involves identifying druggable sites on protein paralogs and using that information to characterize drugs that bind to similar sites on related proteins. By targeting specific paralogs, researchers can potentially develop drugs that have selective effects on different functions within cells. This approach could lead to the development of new treatments for cancer and other diseases, as approximately half of the proteins in human cells have paralogs.
Proteins in the human body have various structures, with some being easier to target with drugs due to obvious binding sites, while others are more difficult to identify. To target a cancer-related protein, the scientists at Scripps Research looked at its paralog, or twin protein, to find a druggable site. By leveraging chemical biology methods, they were able to pinpoint a site on the paralog and then identify drugs that bound to a similar spot on the protein of interest. This allowed them to develop drugs that only interacted with the desired protein, avoiding binding to its highly similar sibling.
The research team focused on the paralog pair CCNE1 and CCNE2, which are overactive in various cancers such as breast, ovarian, and lung cancer. By targeting one protein in the pair, they aimed to potentially improve cancer treatment effectiveness. Since CCNE1 lacked a druggable cysteine, they engineered a cysteine into the protein to mimic the drug-binding spot identified in CCNE2. Through this process, they were able to identify compounds that bound to CCNE1, even in the absence of a cysteine, pointing to a potentially effective way to shut off the protein.
The scientists at Scripps Research discovered multiple compounds that could bind to the same site on CCNE1 without relying on the cysteine. Some of these compounds did not bind to CCNE2, indicating their selective interaction with the desired protein. Additionally, some compounds had opposite functions, stabilizing the protein rather than inactivating it. Structural studies revealed a previously unknown druggable pocket on CCNE1, highlighting the importance of innovative screening methods in drug discovery. Further research is needed to determine the utility of these new compounds in treating cancer and other diseases involving CCNE1.
This study, published in Nature Chemical Biology, was supported by funding from the National Cancer Institute and Pfizer, Inc. The researchers plan to apply their paralog hopping method to other protein pairs involved in tumorigenesis to potentially develop new therapeutic options. By utilizing diverse and creative screening approaches, the team was able to identify functional molecules that could have implications for treating various diseases. This innovative approach could lead to the development of more selective and effective drugs for challenging proteins in the human body.