Leroy Didier, Doerig Christian
Merck-Serono International S.A., Geneva Research Center, 9, Chemin des Mines, Case postale 54, CH-1211 Genève 20, Switzerland.
Trends Pharmacol Sci. 2008 May;29(5):241-9. doi: 10.1016/j.tips.2008.02.005. Epub 2008 Apr 18.
Malaria remains a major killer in many parts of the world. Recently, the development of nonprofit organisations aimed at fighting this deadly scourge incited academic and industrial scientists to merge their expertise in drug-target validation and lead discovery. Expectations are clear: identification and characterisation of new molecules showing high efficacy, low toxicity and little propensity to induce resistance in the parasite. In this context, protein kinase inhibitors represent an attractive possibility. Here, we compare traditional target-based drug-discovery approaches with innovative exploratory paths (parallel screening, cell-based assays, integrated systems biology and allosteric inhibition) and discuss the benefits of acadaemia-industry cooperation. Early characterisation of distribution, metabolism, pharmacokinetic (DMPK) and toxicology parameters are considered as well.
疟疾在世界许多地区仍然是主要杀手。最近,旨在对抗这一致命祸害的非营利组织的发展促使学术和工业科学家将他们在药物靶点验证和先导化合物发现方面的专业知识结合起来。期望很明确:鉴定和表征具有高效、低毒且几乎没有诱导寄生虫产生抗性倾向的新分子。在这种背景下,蛋白激酶抑制剂是一种有吸引力的可能性。在这里,我们将传统的基于靶点的药物发现方法与创新的探索路径(平行筛选、基于细胞的测定、整合系统生物学和变构抑制)进行比较,并讨论学术界与工业界合作的益处。同时也考虑了分布、代谢、药代动力学(DMPK)和毒理学参数的早期表征。