The Ubiquitin Proteasome System: Deja Vu, or Something New?

Summary of the UPS session and interview with Sir Philip Cohen on the subject.Wednesday I attended the 'Where to Find the Drugs: The Ubiquitin Component Systems, Are They the Next Generation Kinases?' Breakout Session, and learned about the extraordinary opportunities and challenges for drug discovery in this area.

Velcade is the first drug targeting the Ubiquitin Proteaseome System (UPS), it was introduced by Millennium in 2007 for multiple myeloma and generated $1B revenue in 2008. While success of a drug targeting a molecular system is often 'paves the way' for future drugs, it was clear from the session that a lot more research is still needed to explore the mechanisms that can be exploited for therapeutics in this area. The UPS is a complex network of enzymes and protein components designed to break down proteins, part of the the important 'ecosystem' necessary to maintain the proper functioning of the cell and prevent malignancy (2006 review).

The borders between the UPS and kinase signaling networks are essentially non-existent, and there are many parallels. The E3 protein components represent the largest family of proteins in the UPS, with 600 members, similar to kinases. There are a wide variety of enzyme functions found in the UPS, which makes it distinct from the kinases, which mostly catalyze one type of reaction. This gives the scope of the mechanisms of action (MOA's) possible more broad for the UPS, and the potential for more specificity. However, it was noted that like the first drug targeting kinases, Gleevec, Velcade shows some non-specificity. Dr. Mark Manfredi, Director of Cancer Pharmacology, Takeda/Millenium, talked about two other drugs targeting the UPS in their pipeline.

MLN 9708 is in clinical trials and has a similar MOA to Velcade, which targets the proteasome, but has a much faster off-rate, meaning it will have greater bioavailability and greater efficacy towards solid tumors. Another Millenium compound in clinical trials is MLN 4924, targeting Nedd8 Activating Enzyme (NAE) of the UPS. NAE is a validated target distinct from the proteasome, and Manfredi commented that there are many unique MOAs to be exploited with the UPS, which is exciting, but this means that more time must be spent with pharmacokinetics and pharmacodynamics (PK/PD) studies in these discovery programs. I had the good fortune to speak with Sir Philip Cohen personally after the session.

Sir Cohen, as the 'father' of kinase biology, and currently spearheading UPS initiatives, has a unique perspective on the path forward for this area. Sir Cohen was the driving force behind the MRC Protein Phosphorylation Unit, which was founded in 1990 towards the goal of understanding the role of protein phosphorylation and cell regulation in disease. The Unit has always interacted closely with academia and industry, perhaps making it one of the original 'translational research' institutions, even before this term existed. Sir Cohen's latest endeavor is the SCottish Institute for ceLL Signalling (SCILLS), where he is building the Protein Ubiquitination Unit first, cherry picking the best and brightest researchers from the UPS field. When I asked him the single most important lesson that he learned in his kinase work, which has helped with understanding the UPS, his answer was more in the organizational aspects than in the science.

Sir Cohen said that "Having a critical mass of leading players is important. Often, in academia, investigators work in silos, which does not advance the field. With the MRC Unit, we pooled grant money and set up teams to do tasks such as DNA cloning and mass spectrometry, allowing the scientists to concentrate on their research." Sir Cohen is clearly very passionate about SCILLS and it will undoubtedly have a big impact on UPS research and the resulting therapeutics. The UPS story will surely have many parallels to that of kinases because the similarities in their science and its ability to provide a cohesive platform amenable to sharing reagents and ideas both within and between organizations. The UPS' increased complexity gives researchers a choice of which component interactions or enzymes to target for drug discovery, which can be seen as both an advantage or disadvantage.

When I asked Sir Cohen about the most promising targets for the UPS, he said that small molecule inhibitors of E2/E3 enzyme complexes are likely to be the best. He indicated that similar to the protein kinases, there are other therapeutic indications such as inflammation which will be an exciting area to watch. Development in the the UPS and kinase areas will likely be synergistic and bode well for important new therapeutics in both. Mary Canady, Ph.D., Founder