Structural and chemical biology in the design of selective kinase inhibitors
Supervisor(s): Professor Julian Blagg and Dr Richard Bayliss
Section of Cancer Therapeutics (including the Cancer Research UK Centre for Cancer Therapeutics)
Teams: Medicinal Chemistry Team One and Mitotic Regulation and Cancer Team
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Summary
Many of the 518 protein kinases in the human kinome are key mediators of signalling pathways crucial to cellular regulation. Aberrant kinase function is a well known component of cancer pharmacology and kinase inhibition via targeting the conserved ATP binding site is a precedented and successful approach to the discovery of small molecule cancer therapeutics [1].
The use of X-ray co-crystal structure determination to understand how small molecules bind to the active site of kinases is a key enabler in drug discovery and medicinal chemistry design [1,2]. The availability of X-ray co-crystal structure information significantly accelerates the drug discovery process by focussing medicinal chemists on optimal vectors for inhibitor optimisation [3].
X-ray structures have shown that kinases adopt multiple conformations: an active, DFG in conformation and many inactive conformations including DFG out. There is currently no rational basis to predict which kinases may adopt a given inactive conformation, or which conformation of a particular kinase might provide the most suitable template upon which to design a selective inhibitor. Our long-term aim is to correct this shortfall by using model kinases to design and test hypotheses that will define the relationships between primary sequence, conformational equilibria and small molecule recognition.
References
1. Van Montfort, R. and Workman, P. (2009) Structure-based design of molecular cancer therapeutics. Trends in Biotechnology Vol 27, No 5, p315
2. Marsden B, Knapp S. (2008) Doing more than just the structure-structural genomics in kinase drug discovery. Current Opinion in Chem Biol. Vol 12, No 1, p40
3. Congreve, M., et al (2005) Structural biology and drug discovery. Drug Discovery Today Vol 10, No 13, p895
