This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: A team of Weill Cornell Medicine investigators has developed a computer model that will help scientists more efficiently develop protein-destroying therapies, a newer type of treatment that is particularly promising for cancer. The study is published July 13 in Nature Communications.
Most drugs use a small molecule to render disease-causing proteins harmless, but protein-degrader therapies aim to destroy the target protein altogether. Eliminating proteins, for example, those with cancer-causing mutations or proteins produced in harmful excess quantities, may offer advantages over disabling a protein. The new model could potentially shave years off the process of developing a new protein-degrader therapy.
"Targeted protein degradation leverages the machinery that already exists in your cells to eliminate unwanted proteins and redirects it to target a disease-causing protein," said senior author Dr. Olivier Elemento, director of the Englander Institute for Precision Medicine and a professor of systems and computational biomedicine at Weill Cornell Medicine. "We developed a framework for determining how to most effectively design a degrader that would destroy the target protein." Protein degraders work by binding to the target protein and to the cellular protein degradation machinery, using a linking molecule to hold the two together.
Until now, the process of developing protein degraders relied on repeated trial and error to determine what works, a time- and resource-intensive process. Wei Du, a former doctoral student in Elemento's laboratory, developed a mathematical model to streamline the process. It allows scientists to identify proteins that would make good targets for a degrader and map the most cost-effective route for degrader optimization.
Elemento explained that the model uses easily obtained laboratory measurements and allows scientists to observe how the degrader would function in a computer model of a cell. "We showed that for protein targets with slow turnover, even relatively weak degrader binding affinity can result in potent degradation," Du said. "We also generated a list of potential targets with high value for degrader development." Protein degraders could be a particularly useful tool to eliminate proteins with cancer-causing mutations, Elemento noted.
For example, a protein that has 200 copies in a normal cell may suddenly have 2,000 due to a cancer-linked mutation. In that case, it is not enough to turn off the protein; it may need to be eliminated or at least reduced to normal levels to prevent damage to organs and tissues caused by excess protein buildup. Du noted that as diverse treatment modalities become available for many diseases, including gene and mRNA therapies, protein degraders and antibody-drug conjugates, it will be important for scientists and clinicians to have mathematical modeling tools that can help them select the best approach for a patient.
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