A research team at the Medical University of South Carolina (MUSC) has discovered a new mechanism for a class of anti-cancer drugs known as E1 inhibitors.
Their findings، published in Nature Communications on December 4، 2018، reveal a novel binding site that will promote drug design of more efficient E1 inhibitors.
The team was led by Shaun Olsen، Ph.D.، an assistant professor of Biology and Molecular Biology at MUSC and a member of the Developmental Cancer Therapeutics Program at Hollings Cancer Center.
Olsen has dedicated his career to solving 3D structures of proteins. Olsen and his team use these protein structures to model interactions with other molecules، including potential new drugs.
In the article، Olsen and his team report that they have discovered a new site on a protein، SUMO E1، which is a target for E1 inhibitors. The new binding site is located in the center of the protein and was previously thought to be out of reach. Olsen's team discovered an alternative conformation of the protein that exposes the site and allows a new inhibitor (COH000; Sumo Biosciences، Inc.، Pasadena، CA) to bind.
"We identified a druggable site on this enzyme that was previously unknown،" says Olsen. "The new inhibitor binding site is completely inaccessible in all previous structures، which is pretty remarkable. E1 structures have been solved before، and this site is hidden in all of them."
E1 inhibitors target the ubiquitin proteasome system (UPS). If you think of a cell as a protein-producing factory، the UPS is the quality control center. The system is responsible for making sure proteins are 'up-to-code' and able to perform their jobs. The UPS helps maintain healthy proteins within the cell; however، when it malfunctions، diseases such as cancer can occur.
There are numerous drugs، both on the market and in clinical trials، that target different parts of the UPS. Proteasome inhibitors، for example، are commonly used to treat multiple myeloma.
Based on preclinical studies، E1 inhibitors show potential as antitumor agents، but there have been obstacles to getting them into the clinic.
"When you develop a drug، you want it to be highly specific for your protein of interest with no cross-reactivity with other targets or proteins، because that can cause negative side effects،" Olsen explains.