Cellular clean-up can also sweep away forms of cancer

13-Nov-2017 - USA

Two new research papers reinforce the benefits of a novel therapy that hijacks the cell’s own protein degradation machinery to destroy cancer cells, Yale researchers report Nov. 9 in the journal Cell chemical biology.

The new approach to drug discovery, called Proteolysis Targeting Chimeras or PROTACs, was developed in the laboratory of Craig Crews, the Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology, professor of chemistry and pharmacology, as well as executive director of the Yale Center for Molecular Discovery.

The system engages the cell’s own protein degradation machinery to destroy targeted proteins by tagging them for removal. Most drugs are based on the ability of small molecules to bind to and block the function of disease-causing proteins, but some proteins are resistant to such intervention.

“This system will help us change the current small-molecule drug paradigm that fails to target 75% of rogue proteins,” said Crews, scientific founder of Arvinas LLC, the New Haven biotechnology company developing the concept.

Original publication

George M. Burslem, Blake E. Smith, Ashton C. Lai, Saul Jaime-Figueroa, Daniel C. McQuaid, Daniel P. Bondeson, Momar Toure, Hanqing Dong, Yimin Qian, Jing Wang, Andrew P. Crew, John Hines, Craig M. Crews; "The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study"; Cell Chemical Biology; 2017

Daniel P. Bondeson, Blake E. Smith, George M. Burslem, Alexandru D. Buhimschi, John Hines, Saul Jaime-Figueroa, Jing Wang, Brian D. Hamman, Alexey Ishchenko, Craig M. Crews; "Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead"; Cell Chemical Biology; 2017

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