Project Portfolio

We have a range of projects at various stages of the drug discovery process. Our overall aims include:

• To identify and validate novel genes and pathways as targets for therapeutic intervention in cancer.
• To utilise innovative synthetic/medicinal chemistry, alongside novel computational and biochemical technologies for drug discovery and development.
• To discover novel mechanism-based drugs and to develop these as rapidly as possible from the laboratory bench through to early clinical trials.
• As a result, provide new diagnostic and therapeutic agents for the treatment of human cancers.

Case study: The identification of a selective CDK7 inhibitor

Normal progression through the cell cycle requires the sequential action of a family of regulatory enzymes called the cyclin-dependent kinases (CDKs). Direct or indirect deregulation of CDK activity in cells is a feature of almost all cancers, which has prompted a search for CDK inhibitors as anti-cancer agents. The CDK protein 7 is one particular family member that plays a critical role in regulating cell cycle by both activating other CDK enzymes, and regulating gene transcription as part of the TFIIH transcription factor. It is therefore a highly attractive target for the development of anti-cancer drugs.

In collaboration with Professors Dennis Liotta and James Snyder at Emory University (Atlanta, USA), who lead the most productive drug-discovery and development academic group in the USA, computer modelling studies were carried out on the CDK7 structure, to rationally design potent and selective CDK7 inhibitors. The subsequent iterative cycle of design, chemical synthesis and biological assessment, resulted in the discovery of an inhibitor that is both highly potent against CDK7 (IC50 = 21 nM), and significantly selective for this CDK. This is the first selective CDK7 inhibitor reported, and importantly it was shown to inhibit the growth of cancer cell lines and showed antitumor in vivo.

 

Key group publications

“The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells.” Thiruchelvam PT, et al. Breast Cancer Res Treat. 2011 Jun;127(2):385-96. Epub 2010 Jul 6. PMID: 20607599. doi: 10.1007/s10549-010-0994-9

“Transient over-expression of estrogen receptor-alpha in breast cancer cells promotes cell survival and estrogen-independent growth.” Tolhurst RS, et al. Breast Cancer Res Treat. 2010 Aug 22. [Epub ahead of print] PMID: 20730598. doi: 10.1007/s10549-010-1122-6

“A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration.” Heathcote DA, et al. J. Med. Chem. 2010, 53, 8508-22. doi: 10.1021/jm100732t

“Concise, flexible syntheses of 4-(4-imidazolyl)pyrimidine cyclin-dependent kinase 2 (CDK2) inhibitors.” Toumi, M, et al. Tetrahedron Lett. 2010, 51, 6126–6128. doi: 10.1016/j.tetlet.2010.09.074

“SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and -2” Peck, B.; Chen, C. –Y.; Ho K. K.; Di Fruscia, P.; Myatt, S. S.; Coombes, R. C.; Fuchter, M. J..; Hsiao, C. –D.; Lam, E. Mol. Cancer Ther. 2010, 9, 844-855. doi: 10.1158/1535-7163.MCT-09-0971.

“The development of a highly selective inhibitor of cyclin-dependent kinase 7 (CDK7) which demonstrates anti-tumor activity.” Ali, S.; Heathcote, D. A.; Kroll, S. H. B.; Jogalekar, A. S.; Scheiper, B.; Patel, H.; Brackow, J.; Siwicka, A. Fuchter, M. J. Periyasamy, M.; Tolhurst, R. S.; Kanneganti, S. K.; Snyder, J. P.; Liotta, D. C.; Aboagye, E. O.; Barrett, A. G. M.; Coombes, R. C. Cancer Res. 2009, 69, 6208-6215. doi: 10.1158/0008-5472.CAN-09-0301