UK companies pair on libraries targeting the ubiquitin system

 

The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system, according to the National Center for Biotechnology Information. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation and endocytosis. The ubiquitin system has been implicated in the immune response, development and programmed cell death.

 

In this collaboration, Ubiquigent comes to the table with its biology expertise, while Cyclofluidic displays its chemistry platform to develop the comprehensive library, according to a June 3 news release.

 

Key to the collaboration is Cyclofluidic’s CyclOps platform, which integrates flow chemistry, purification, screening and drug design, utilizing machine-learning algorithms to allow drug lead molecules to be assayed in minutes, rather than weeks, after they are designed. The team has shown that use of the platform reduces timelines for hit-to-lead optimization by 50 percent, allowing molecules to progress into preclinical studies faster.

 

“We are very pleased to be entering into this relationship with Cyclofluidic, as we believe that our combined approach will uncover many exciting opportunities in this rapidly developing field,” Jason Brown, managing director of Ubiquigent, stated in a news release. “This latest collaboration further supports Ubiquigent’s goal of being the first ubiquitin system-focused, fully integrated provider of biology, assays, small-molecule libraries and compound profiling services.”

 

Jason Mundin, commercial director of Ubiquigent, tells DDNews: “The ubiquitin system offers many new drug discovery target opportunities across multiple therapeutic areas. Involving the modification of proteins through the attachment of the protein ubiquitin, or ubiquitin-like proteins (Ubls), ubiquitylation and related Ubl modifications are key to the control of cellular protein homeostasis as well as signaling, akin to the critical role played by phosphorylation—approximately 30 percent of commercial drug discovery programs target phosphorylation enzymes—and holds similar potential for clinical utility.”

 

The goal of the collaboration is “to build novel ubiquitin system-targeted compound libraries that will represent ‘start-points’ for ubiquitin-focused drug discovery programs,” Mundin adds. “The output of the collaboration will be jointly commercialized by the companies.”

 

Furthermore, the collaboration is “open-ended and will continue as long as it’s successful,” Mundin says, adding, “One of the challenges with the ubiquitin field is the chemistry. This is similar to the situation in the kinase field a number of years ago. As with the kinase area, we are convinced that the chemistry is possible and that it will open up many new opportunities for points of therapeutic intervention across multiple therapeutic areas. Part of our strategy at Ubiquigent is to collaborate with groups that we feel have the potential to tackle this challenge so we can combine their chemistry with our biology, thus our collaboration with Cyclofluidic.”

 

Mundin anticipates they will be able to start screening compounds later this year.

 

“Currently we don’t have any particular therapeutic focus, but as and when compounds start to emerge, we will be looking to take them into therapeutically relevant assay systems and models either prior to or part of our commercialization strategy,” he notes.

 

Dave Parry, chief operating officer of Cyclofluidic, states: “We are excited by the opportunity to demonstrate the advantages of our CyclOps platform in accelerating discovery to this rapidly evolving area of biology, which has been made possible through access to Ubiquigent’s leading expertise in the field.”

 

“The main focus for the collaboration is to generate new chemistry libraries for ubiquitin targets which will aid the research community in providing tools and leads to continue to develop this important emerging area of disease biology,” Parry says.

 

In October 2008, Cyclofluidic, a breakthrough technology company, was established with the aim of significantly accelerating the drug discovery process by allowing researchers to test a greater range of potential new medicines in a shorter time. The UK government’s Innovate UK agency, then called the Technology Strategy Board, helped facilitate this innovative arrangement between Pfizer and UCB and will continue to support Cyclofluidic by co-funding its R&D. The aim of Cyclofluidic is to develop technologies that automate and integrate processes known as flow chemistry and flow biology to help pharmaceutical companies shorten timelines in drug development.

 

In late 2014, Ubiquigent struck a deal not unlike the one with Cyclofluidic with the Drug Discovery Unit (DDU) of the University of Dundee to develop and market new ubiquitin system-targeted compound libraries aimed at discovering potent and selective therapeutics across such areas as cancer, cardiovascular and metabolic, neurological and musculoskeletal and infection and immunity. Under the terms of the agreement, Ubiquigent and the DDU will design, develop and characterize small-molecule compound libraries targeting the intracellular proteins of the ubiquitin system to provide a valuable source of novel targeted libraries to unlock new medicinal chemistry opportunities.