Protein kinases have proven to be very attractive drug targets. In the hypertension arena, WNK kinases and their substrates have been highlighted as promising targets for developing new anti-hypertensive drugs with novel mechanisms of action. Currently, we have a good understanding of the WNK signalling pathway (see references), which we can use in designing small molecules that manipulate WNK kinases and their substrates.
This project will therefore focus on the design, synthesis and biological evaluation of small molecules that inhibit WNK kinases and their substrate, i.e. SPAK and OSR1 kinase. This work will involve 1) the development of fluorescence-based screening assays for identifying hit compounds that inhibit the activity of WNK1, OSR1 and SPAK kinases, 2) the optimisation of such hits to improve their efficacy and drug-like properties by synthesising other small molecules derived from the hit compound, and 3) setting up assays for measuring the activities of these compounds in vitro and in vivo.
From working on this project, the PhD candidate will learn the synthesis, purification and characterisation of small molecules, drug design and development as well as assay development for testing the biological activities of synthetic molecules. Such knowledge will be extremely valuable for those wishing to pursue a career in academia or with pharmaceutical/biotechnology companies.
The work will be based at the School of Chemistry with very close collaboration with the School of Clinical and Experimental Medicine, University of Birmingham.
Contact Dr. Youcef Mehellou ([email protected]
) for informal inquiries.
• Ohta, A., Schumacher, F.R., Mehellou, Y., Johnson, C., Knebel, A., Macartney, T.J., Wood, N.T., Alessi, D.R., Kurz, T, 2013, The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms; disease-causing mutations in KLHL3 and WNK4 disrupt interaction. Biochem. J., In Press doi:10.1042/BJ20121903.
• Mehellou, Y., Alessi, D.R., Macartney, T.J., Szklarz, M., Knapp, S., Elkins, J.M., 2013, Structural insights into the activation of MST3 by MO25, Biochem. Biophys. Res. Commun. 431, 604-609.
• Thastrup, J.O., Rafiqi, F.H., Vitari, A.C., Pozo-Guisado, E., Deak, M., Mehellou, Y., Alessi, D.R., 2012, SPAK/OSR1 regulate NKCC1 and WNK activity: analysis of WNK isoform interactions and activation by T-loop trans-autophosphorylation, Biochem. J. 441, 325-337.
• Filippi, B.M., de los Heros, P., Mehellou, Y., Navratilova, I., Gourlay, R., Deak, M., Plater, L., Toth, R., Zeqiraj, E., Alessi, D.R., 2011, MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 protein kinases. EMBO J. 30, 1730-1741.