Drug Discovery Unit, College of Life Sciences, James Black Centre, University of Dundee, Dundee, DD1 5EH, UK.
ChemMedChem. 2011 Dec 9;6(12):2214-24. doi: 10.1002/cmdc.201100344. Epub 2011 Sep 13.
New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of ~3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3-cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3-CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2.
迫切需要新的药物来治疗热带寄生虫病，如利什曼病和非洲人类锥虫病（HAT）。这项工作涉及对一组约 3400 种化合物的聚焦激酶进行高通量筛选，以鉴定有效的、对寄生虫具有选择性的酶类利什曼 CRK3-细胞周期蛋白 6 复合物抑制剂。本研究旨在从化学角度验证利什曼 CRK3-CYC6 是一个药物靶点。确定了 8 个命中系列，其中 4 个进行了后续研究。通过对这些系列进行经典的 SAR 研究进行优化，得到了对密切相关的人细胞周期蛋白依赖性激酶 CDK2 具有显著选择性的低纳摩尔 CRK3 抑制剂。
