A newly published study from Yale University details the discovery of a new type of drug, called Proteolysis Targeting Chimeras (PROTACs), which can target all disease-causing proteins.
Current drugs block the actions of only about a quarter of known disease-causing proteins, but Yale University researchers have developed a technology capable of not just inhibiting, but destroying every protein it targets.
The new type of drug, called Proteolysis Targeting Chimeras (PROTACs), also can continue to destroy mutant proteins in mouse tumors, according to a new study published on June 10, 2015, in the journal Nature Chemical Biology.
“This new drug modality culminates a decade of work in the field by my lab,” said Craig Crews, the Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology and senior author of the paper, which was done in collaboration with scientists from GlaxoSmithKline and Arvinas, LLC.
Almost all current drugs are small molecules designed to fit into the folds of disease-causing proteins and inhibit their function. High doses are often needed to ensure that protein function is blocked sufficiently to produce therapeutic results, which in turn can produce harmful side effects.
In contrast, PROTACs engage the cells’ own protein degradation machinery to destroy targeted proteins by tagging them for removal and can do so multiple times, meaning it can work at lower doses, the authors say. This suggests this new type of drug has not only the potential to target proteins that are not currently “pharmaceutically vulnerable” but could do so safely, Crews said.
“This is a game-changer for drug development,” Crews said.
Reference: “Catalytic in vivo protein knockdown by small-molecule PROTACs” by Daniel P Bondeson, Alina Mares, Ian E D Smith, Eunhwa Ko, Sebastien Campos, Afjal H Miah, Katie E Mulholland, Natasha Routly, Dennis L Buckley, Jeffrey L Gustafson, Nico Zinn, Paola Grandi, Satoko Shimamura, Giovanna Bergamini, Maria Faelth-Savitski, Marcus Bantscheff, Carly Cox, Deborah A Gordon, Ryan R Willard, John J Flanagan, Linda N Casillas, Bartholomew J Votta, Willem den Besten, Kristoffer Famm, Laurens Kruidenier, Paul S Carter, John D Harling, Ian Churcher and Craig M Crews, 10 June 2015, Nature Chemical Biology.
The PROTAC technology is being commercialized by New Haven biotechnology company Arvinas, LLC, which recently signed a $434 million partnership from pharmaceutical giant Merck to further explore the potential of the PROTAC technology.
Crews is scientific founder of Arvinas, LLC and Proteolix, Inc., which developed the next generation multiple myeloma drug Kyprolis based on work from his lab. The study was funded by the National Institutes of Health and GlaxoSmithKline.