Paul Clarke
Senior Researcher
Signal Transduction and Molecular Pharmacology
The Institute Of Cancer Research
United Kingdom
Biography
Over the last 10 years Dr Clarke’s research has contributed to the discovery of the structure and function of a key cancer molecule, Hsp90, and drugs which target this protein. The significance of this pioneering research was recognised by the award of the prestigious Cancer Research UK Translational Cancer Research Prize (2013) and Dr Clarke was a member of this team of senior scientists. Dr Clarke takes particular responsibility for mechanistic molecular pharmacology studies and the discovery of biomarkers of drug action, with a special focus on molecular chaperones and the PI3 kinase pathway. He has a high level of expertise in the combined use of chemical tools and molecular genetic technologies to identify and validate new drug targets and to discover and validate predictive and mode of action biomarkers for drugs that inhibit these targets. The molecular chaperone Hsp90 is a stress-regulated protein that contributes to protein quality control by maintaining the activity of client proteins that are fundamentally important in cancer. Inhibiting Hsp90 has pleiotropic effects, undermining cancer cell growth, survival and metastasis. Dr Clarke’s research has contributed to the discovery of drugs that target Hsp90. One of these drugs, AUY922, has shown promising activity in clinical trials in drug-resistant breast and non-small cell lung cancers. Dr Clarke has also contributed to the research of teams developing drugs targeting oncogenic signal transduction, including the discovery of the leading PI3 kinase inhibitor GDC-0941, which is now showing promising activity in clinical trials.
Research Interest
Overall, Dr Clarke aims to contribute to the wider goal of the Cancer Research UK Cancer Therapeutics Unit to improve the lives of cancer patients through the discovery and development of personalised molecular medicines.
Publications
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Mallinger, A., Schiemann, K., Rink, C., Sejberg, J., Honey, M.A., Czodrowski, P., Stubbs, M., Poeschke, O., Busch, M., Schneider, R., et al. (2016). 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19. Acs medicinal chemistry letters, Vol.7(6), pp. 573-578.
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Clarke, P.A., Ortiz-Ruiz, M.-., TePoele, R., Adeniji-Popoola, O., Box, G., Court, W., Czasch, S., El Bawab, S., Esdar, C., Ewan, K., et al. (2016). Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases. Elife, Vol.5.
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Vaughan, L., Clarke, P.A., Barker, K., Chanthery, Y., Gustafson, C.W., Tucker, E., Renshaw, J., Raynaud, F., Li, X., Burke, R., et al. (2016). Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors. Oncotarget, Vol.7(36), pp. 57525-57544.
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Pawlyn, C., Bright, M.D., Buros, A.F., Stein, C.K., Walters, Z., Aronson, L.I., Mirabella, F., Jones, J.R., Kaiser, M.F., Walker, B.A., et al. (2017). Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. Blood cancer journal, Vol.7(3), pp. e549-e549.
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Agliano, A., Balarajah, G., Ciobota, D.M., Sidhu, J., Clarke, P.A., Jones, C., Workman, P., Leach, M.O. & Al-Saffar, N.M. (2017). Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy. Oncotarget, Vol.8(29), pp. 47969-47983.
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Whittaker, S.R., Mallinger, A., Workman, P. & Clarke, P.A. (2017). Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacology & therapeutics, Vol.173, pp. 83-105.
