ITI Life Sciences completed an report last year that looked at a range of emerging drug targets. That report identified targets within the ubiquitin proteasome system (UPS) as an area where scientific interest has grown fast over recent years, yet "it remains an unexploited and largely unchartered area for drug discovery."

Following a subsequent, second, report on UPS targets specifically, ITI Life Sciences has now issued a 'Call for Expressions of Interest' from experts in the field of ubiquitin signalling. Once the deadline in July has passed, the ITI Life Sciences plan to fund a drug discovery project based on these targets.

There is a well established trend across the pharmaceutical industry, of a decreasing number of truly innovative drugs, with many copycat or 'me-too' compounds in company pipelines. Novel chemical entities are more often at an early stage of development and therefore licensing deals are often done at an earlier stage.

However, early stage research is less likely to attract investment and ITI Life Sciences hopes to plug this gap with its funding awards, aimed at establishing new collaboration projects, for example between academics and industry players.

"We believe ubiquitin signaling is a very exciting area for drug discovery R&D, but at present it has not yet reached a level to attract substantial venture capital funding," said Eleanor Mitchell, Acting CEO of ITI Life Sciences.

"However, it is at the right stage of development for ITI Life Sciences to fund, as we are uniquely poised to bridge the funding gap between academic and commercial R&D. We look forward to receiving applications from the global scientific community to participate in this exciting opportunity."

Barry Middleton, of ITI Life Sciences, wrote the report on the UPS. He explained to DrugResearcher.com that the organisation is not taking a parochial view with the funding, and would welcome applications from anywhere in the world, not just Scotland.

ITI Life Sciences has already awarded £50m to five different projects at an average of £5m to £10m and will be looking to give a similar amount in this latest project.

"Some of those established projects are drawing to a close so we are feeding the pipeline," said Middleton.

A Challenging target

Several companies are actively researching the UPS. The system was discovered in 1980 and implicated in key protein degradation mechanisms via a small protein named ubiquitin. A resultant Nobel prize in 2004 coincided with ubiquitin being linked to a range of additional key cellular functions and diseases including cancer, neurodegenerative, metabolic, inflammatory and infectious diseases.

In fact, the Nobel laureates in question now act as scientific advisors to one of those companies, namely Proteologics. Other companies active in the area include Rigel, Cytogen, Regeneron and Topotarget. Larger pharma and biotech companies are also 'dipping their toe' in the water: Genentech, Roche and Novartis are also examining ubiquitin pathways.

However, it is a challenging system to target. Ubiquitin is a small protein used to label old, damaged, or malformed proteins for destruction by the proteasome.

The only approved UPS-related therapeutic is Millennium Pharmaceuticals' Velcade (bortezomib). The proteasome inhibitor is approved for use in myeloma but has multiple undesirable side effects, including heart, liver and kidney problems. These are thought to be caused by the drugs broad ranging effects on general protein degradation.

Middleton explained that the UPS is a very hierarchical system. Upsteam of the proteasome are E1 ubiquitin activating enzymes, E2 ubiquitin conjugating enzymes and E3 ubiquitin ligases and deubiquinating enzymes (DUBs).

This latter class of targets is perhaps the most obvious one for therapeutic intervention, given the number of ligases identified (around 600) and their primary role in controlling substrate specificity within the UPS. However, drug design is still difficult as the compounds must attempt to interfere with multiple, large protein-protein interaction sites.

DUBs are also a promising candidate a target because they are more easily affected by small molecules, according to Middleton.

He went on to say that ITI Life Sciences hope to have completed the process and announced the recipient of the funding by the end of the year at the latest.