Merck has weathered some neuroscience setbacks in recent years, but it’s picked up new programs through licensing and M&A. Its latest deal? An R&D pact with Almac Discovery centered on deubiquitinases, a family of enzymes that play many roles in cellular regulatory processes.
Under a two-year partnership, the duo will identify and develop small molecule inhibitors of deubiquitinases, or DUBs, for the treatment of neurodegenerative diseases. Merck will pick up lead optimization, preclinical and clinical development and commercialization. They did not disclose financial terms or specific disease areas of interest.
“There are some clear, neural pathological processors that both collaborators are very interested in and believe there is a fundamental role for certain [DUB-targeting] molecules,” Alan Lamont, Ph.D., Almac Discovery’s vice president of business development and licensing, told FierceBiotech. “We are looking at exploring those pathological processes. We clearly could have applications across a range of neurodegenerative diseases, but at this point, we’re not disclosing specific diseases.”
At their core, DUBs remove ubiquitin from proteins and other molecules. Ubiquitin itself is a protein that cells use to tag damaged or unneeded proteins for degradation in a protein complex called a proteasome. But that’s not ubiquitin’s only job, said Xavier Jacq, Almac Discovery’s VP of biology.
“It is also modifying the activity and the localization of the protein, so it’s a very generic mode of regulating the activity of many proteins in cells,” Jacq said. “And ‘in cells’ is really the key parameter; ubiquitination is only happening inside cells … It’s not something that happens outside of cells.”
So, DUBs are involved in many different processes, including other kinds of protein degradation, namely lysosomal degradation and autophagy, often called the cell’s “garbage disposal.” They also play a big role in the immune response, Tim Harrison, Almac Discovery’s VP of discovery chemistry, said.
Other companies are working on protein-degrading drugs that target the ubiquitin proteasome system. But targeting DUBs rather than the protein degradation machinery itself opens up pathways that use ubiquitin to modify proteins but in processes that do not degrade them.
“DUBs will provide additional options for the field to answer a number of therapeutic questions,” Jacq said.
The deal comes five months after Merck snapped up Calporta Therapeutics for up to $576 million to get its hands on TRPML1 agonists, designed to treat neurodegenerative disorders by clearing toxic proteins from the brain. The Big Pharma made the acquisition after verubecestat failed studies in prodromal and mild to moderate Alzheimer’s disease, meeting the same fate as other BACE inhibitors.