Bitopic protein kinase inhibition - a new paradigm in drug discovery

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Studentship strategic priority area: Therapeutics and nanomedicineKeywords:Medicinal chemistry, bitopic kinase inhibitors, protein kinases, malariaProtein kinases are considered a major drug target for a range of human diseases. The barrier to drug development is in designing drugs that distinguish the target kinase from the other 550 protein kinases in the human genome. We have discovered that the human malaria parasite, Plasmodium falciparum, requires the activity of a parasite kinase, PfCLK3, to survive. Working together with GlaxoSmithKline we have discovered a selective inhibitor to PfCLK3 that binds both to the catalytic domain of the kinase but also to an allosteric site. This highly novel bitopic mode of action offers a new paradigm in selectively targeting protein kinases. By employing chemical design and synthesis to the generation further bitopic probes to PfCLK3 in concert with molecular parasitology and chemical genetic engineering of malarial parasites we will not only define the biological function of PfCLK3 but importantly will test the novel hypothesis that protein kinases can be selectively targeted by biotopic molecules that dually act at allosteric and catalytic sites. This PhD plugs the gap between chemistry and biology, aligning closely with EPSRC and MRC initiatives of technologies touching life and engineering for health and life sciences as well as the ODA and global health challenges.