- Combinatorial domain hunting technology aids identification of MEK protein suitable for structure-based drug discovery
- New structural information allowed UCB scientists to design a novel class of molecules which inhibit MEK
Slough/ Cambridge, UK, 12th March 2012: UCB and Domainex Ltd, a UK-based drug discovery company, have jointly published the results of a collaboration in the field of cancer drug discovery. Working together, the two companies have developed an experimental system to study the three-dimensional structure of Mitogen-activated protein kinase kinase (MAPKK, also known as MEK), a protein which is over-active in many human cancers. Using the high-resolution structural information, UCB scientists were able to design a novel class of molecules which inhibit MEK and which have the potential to combat cancer.
The key step in this work, reported in the latest edition of the Journal of Structural Biology, used Domainex’s Combinatorial Domain Hunting (CDH) technology to identify a form of the MEK protein which can be produced in large quantities and which is suitable for structure-based drug discovery. In the case of MEK, this was challenging because conventional methods proved unsuccessful, however Domainex’s CDH technology allowed the problem to be solved rapidly.
“The partnership with Domainex has been invaluable for our MEK discovery program. Successful collaborations, such as this, are a key part of UCB’s innovative and cutting-edge research. We hope that the novel class of MEK inhibitors which the UCB team discovered will bring benefits to patients,” said Neil Weir, Senior Vice President, Discovery Research UCB.
CDH is a biotechnological method that enables the identification of proteins for drug discovery and other applications. It involves the random fragmentation of DNA, and the screening of thousands of DNA fragments to identify those that produce large amounts of the protein of interest.
Trevor Perrior, Research Director at Domainex said: “Producing high-quality protein is crucial for successful drug research. Once again, Domainex’s CDH technology has proven to be invaluable, and the rapid identification of the best form of MEK from tens of thousands of other possibilities further validates our technology. We were extremely pleased that UCB could successfully utilize the constructs to generate high-resolution structural information and, most importantly, to use it to optimize their chemical series.”
UCB, Brussels, Belgium (www.ucb.com) is a global biopharmaceutical company focused on the discovery and development of innovative medicines and solutions to transform the lives of people living with severe diseases of the immune system or of the central nervous system. With more than 8,000 people in about 40 countries, the company generated revenue of EUR 3.2 billion in 2011. UCB is listed on Euronext Brussels (symbol: UCB).
Forward looking statements: UCB
This press release contains forward-looking statements based on current plans, estimates and beliefs of management. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial information, expected legal, political, regulatory or clinical results and other such estimates and results. By their nature, such forward-looking statements are not guarantees of future performance and are subject to risks, uncertainties and assumptions which could cause actual results to differ materially from those that may be implied by such forward-looking statements contained in this press release. Important factors that could result in such differences include: changes in general economic, business and competitive conditions, the inability to obtain necessary regulatory approvals or to obtain them on acceptable terms, costs associated with research and development, changes in the prospects for products in the pipeline or under development by UCB, effects of future judicial decisions or governmental investigations, product liability claims, challenges to patent protection for products or product candidates, changes in laws or regulations, exchange rate fluctuations, changes or uncertainties in tax laws or the administration of such laws and hiring and retention of its employees. UCB is providing this information as of the date of this press release and expressly disclaims any duty to update any information contained in this press release, either to confirm the actual results or to report a change in its expectations.
There is no guarantee that new product candidates in the pipeline will progress to product approval or that new indications for existing products will be developed and approved. Products or potential products which are the subject of partnerships, joint ventures or licensing collaborations may be subject to differences between the partners. Also, UCB or others could discover safety, side effects or manufacturing problems with its products after they are marketed.
Moreover, sales may be impacted by international and domestic trends toward managed care and health care cost containment and the reimbursement policies imposed by third-party payers as well as legislation affecting biopharmaceutical pricing and reimbursement.
Domainex uses unique and proprietary technologies to resolve common bottlenecks facing the pharmaceutical and biotechnology industries in the post-genomic era. Major discovery 'gaps' exist between the vast amount of genomic information that is now available, the accessibility of the corresponding proteins for use in target validation and drug discovery, and the identification of robust hits in a cost effective manner. Founded in 2001, Domainex is a privately owned company based in Cambridge, UK.
Domainex has developed a discovery platform, which enables rapid progression of drug discovery projects from novel target through to Candidate Drug by means of its Combinatorial Domain Hunting technology, LeadBuilder virtual hit screening software, and its integrated approach to medicinal and computational chemistry.
Domainex’s patented CDH technology enables the cloning and expression of soluble drug target protein domains in E. coli, followed by the identification of those constructs that are able to bind a ligand. This enables binding assays to be developed, facilitating hit identification studies. In only 3-4 months, all expressible ligand binding domains of a target protein are identified (from libraries of 20,000-100,000 constructs), enabling key rate limiting steps in early drug discovery to be easily overcome and resulting in large time savings over standard approaches.
Domainex has also developed LeadBuilder - a virtual screening approach for targets which is specifically aimed at quickly identifying hit molecules that are ideally suited for further development.
The experienced medicinal chemistry team has a proven track record in supporting biotech or university groups by providing expertise to take hit compounds through lead optimization and on to candidate selection. Three compounds to date arising from these collaborations are currently in clinical evaluation, with two additional drugs in preclinical studies.
1. Meier C, Brookings DC, Ceska TA, Doyle C, Gong H, McMillan D, Saville GP et al. Engineering human MEK for structural studies: A case study of combinatorial domain hunting. Journal of Structural Biology (2012); 177:329-34.