Phosphorylation, Ubiquitylation and Drug Discovery
Phosphorylation, Ubiquitylation and Drug Discovery

It has been estimated that approximately 30% of current R&D spend in pharmaceutical companies is focused on the development of kinase inhibitors.

In the field of cancer, protein kinases have become the pharmaceutical industry’s most important class of drug target. To date, about 25 drugs targeting protein kinases have been clinically approved for use in cancer (see table below or as a pdf to view structures at a higher resolution). They include Gleevec, an inhibitor of the Bcr-Abl tyrosine kinase, which has transformed chronic myelogenous leukaemia from a disease that was rapidly fatal into a manageable condition.

Importantly, the first protein kinase inhibitor for a non-oncological application namely Pfizer’s JAK3 inhibitor tofacitinib (CP-690550) has been approved by the FDA in November2012 for the treatment of rheumatoid arthritis and other inflammatory diseases. A JAK1/JAK2 inhibitor called Ruxolitinib (INCB18424) generated by Incyte Pharmaceuticals’ is expected to be licensed shortly. There is expectation that these JAK inhibitors may be more effective than anti-TNF therapies such as the Humira antibody, which has sales approaching US$8 billion.

The development of JAK inhibitors represent another landmark in the field of kinase inhibitor research, as they represent the first kinase inhibitors to be approved for treatment of a disease other than cancer. We expect their approval to spark a new upsurge of interest in the targeting of protein kinases as drug targets outside the area of oncology, similar to the way in which the 2001 approval of Gleevec stimulated huge pharmaceutical investment in protein kinases as anti-cancer targets.

The current global market for kinase therapies is about US$18 billion per annum, forecast to at least double by 2025. There are over 100 small-molecule kinase inhibitors active in clinical development and many more are likely to be approved in the coming years assuring that there will remain a great interest to better understanding the roles that protein kinases play in human diseases for the foreseeable future.

Small molecular inhibitors of protein kinases approved for clinical use by the FDA (Updated June 2016)(PDF)

Abbreviations: ALL, Acute Lymphoblastic Leukaemia, GIST, Gastro-Intestinal Stromal Tumour, NSCLC, Non-Small Cell Lung Carcinoma


The enzymes that regulate reversible protein ubiquitylation are as numerous as protein kinases and there is great expectation that the ubiquitin system could provide just as many if not more drug targets. Although industrial interest in targeting the ubiquitin system for drug discovery has lagged far behind protein phosphorylation, there is already one approved drug (Velcade/Bortezomib) that targets a component of the ubiquitin system, as well as 14 others undergoing clinical trials. Global sales of Velcade/Bortezomib in 2009 reached US$1.4 billion. It would be very surprising if pharmaceutical activity in the ubiquitin system did not see similar growth over the next decade.

Although we know the identity of most of the circa 1000 proteins that are likely to be players in regulating ubiquitylation pathways, there is little information on which components in these pathways would represent the best targets for treatment of disease. Most have not been studied in depth and few have been knocked out in mice. A key aim for the MRC-PPU will be to advance understanding of the role of ubiquitylation and related modifications in cell regulation and human disease, and then to define and validate which components might represent the best drug targets. Another key remit of our research will be to generate reagents and improve technologies that will help to advance ubiquitylation research.

In order to stimulate interest from the pharmaceutical industry, we have recently taken steps to broaden the remit of our DSTT collaboration with the Pharmaceutical industry which from July 2012, encompasses the study of the phosphorylation ubiquitylation system. We are also involved in the MRC International Mouse Phenotyping Consortium to generate and characterise the phenotypes of around 150 key disease-linked gene knock-outs that encode components of the ubiquitylation system. We are excited about the potential of this new consortium and expect it to lead to essential new understanding of the physiological processes that are controlled by components of the ubiquitylation system. This can only accelerate our understanding of the ubiquitin system and help pinpoint possible drug targets. The knock-out mice and cell lines derived from the consortium will be made available to all academic and industry researchers to enhance understanding of the ubiquitin system. We are also working closely with our pharmaceutical collaborators to ensure that the MRC Mouse Phenotyping Consortium analyses targets of high priority to drug discovery efforts.