Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London, U.K. W12 0BZ.
School of Chemistry, University of Leeds, Leeds, U.K. LS2 9JT.
J Med Chem. 2020 Jul 23;63(14):7740-7765. doi: 10.1021/acs.jmedchem.0c00570. Epub 2020 Jul 14.
The leishmaniases, caused by species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. -Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising anti-leishmanial target. Here we describe a comprehensive structure-activity relationship (SAR) study of a thienopyrimidine series previously identified in a high-throughput screen against NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay, we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (), a compound with modest activity against intracellular amastigotes and excellent selectivity (>660-fold) for NMT over human NMTs.
利什曼病是由原生动物寄生虫引起的，是被忽视的热带病，在全球范围内有数百万人患病。目前的治疗方法受到毒性、耐药性和成本的限制。-肉豆蔻酰基转移酶（NMT），一种在所有真核生物中普遍存在且必不可少的酶，已通过遗传和药理学方法验证为一种有前途的抗利什曼原虫靶点。在这里，我们描述了之前在针对 NMT 的高通量筛选中鉴定出的噻吩并嘧啶系列的全面结构-活性关系（SAR）研究，该系列跨越了酶和细胞测定格式中的 68 种化合物。使用化学标记靶标结合生物标志物测定法，我们确定了该系列中第一个在利什曼原虫寄生虫中具有靶标 NMT 活性的抑制剂。此外，与 NMT 复合物的 12 种衍生物的晶体结构分析揭示了对于未来基于结构的优化很重要的关键因素，从而得到 IMP-105（），一种对细胞内无鞭毛体具有适度活性且对 NMT 具有出色选择性（超过 660 倍）的化合物。
