Bitopic protein kinase inhibition - a new paradigm in drug discovery

学生战略优先领域：治疗学和纳米医学关键词：药物化学、蛋白激酶抑制剂、蛋白激酶、疟疾蛋白激酶被认为是治疗一系列人类疾病的主要药物靶点。药物开发的障碍是设计药物，将目标激酶与人类基因组中的其他550种蛋白激酶区分开来。我们已经发现，人类疟疾寄生虫恶性疟原虫需要寄生虫激酶PfCLK3的活性才能生存。与葛兰素史克合作，我们发现了一种PfCLK3的选择性抑制剂，它既能与激酶的催化域结合，也能与变构位点结合。这种非常新颖的点位作用模式为选择性靶向蛋白激酶提供了一个新的范例。通过使用化学设计和合成来产生针对PfCLK3的进一步的比位探针，结合分子寄生虫学和疟疾寄生虫的化学基因工程，我们不仅将定义PfCLK3的生物学功能，而且重要的是将检验新的假设，即蛋白激酶可以被在变构和催化位置双重作用的生物分子选择性地靶向。该博士学位填补了化学和生物学之间的差距，与EPSRC和MRC关于接触生命的技术和工程用于健康和生命科学以及官方发展援助和全球健康挑战的倡议密切一致。

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.