School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow G12 8QQ, U.K.
Centre for Translational Pharmacology, Institute of Molecular Cell and Systems Biology, University of Glasgow, Davidson Building, Glasgow G12 8QQ, U.K.
J Med Chem. 2020 Sep 10;63(17):9300-9315. doi: 10.1021/acs.jmedchem.0c00451. Epub 2020 Aug 11.
The protein kinase CLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage . We recently validated CLK3 as a drug target in malaria that offers prophylactic, transmission blocking, and curative potential. Herein, we describe the synthesis of our initial hit TCMDC-135051 and efforts to establish a structure-activity relationship with a 7-azaindole-based series. A total of 14 analogues were assessed in a time-resolved fluorescence energy transfer assay against the full-length recombinant protein kinase CLK3, and 11 analogues were further assessed in asexual 3D7 (chloroquine-sensitive) strains of parasites. SAR relating to rings A and B was established. These data together with analysis of activity against parasites collected from patients in the field suggest that TCMDC-135051 is a promising lead compound for the development of new antimalarials with a novel mechanism of action targeting CLK3.
蛋白激酶 CLK3 在疟原虫 RNA 剪接的调控中起着关键作用，对血期寄生虫的生存是必需的。我们最近验证了 CLK3 是疟疾的一个药物靶点，具有预防、阻断传播和治疗的潜力。在此，我们描述了我们最初的命中化合物 TCMDC-135051 的合成，并努力建立基于 7-氮杂吲哚的系列化合物的构效关系。总共评估了 14 个类似物对全长重组蛋白激酶 CLK3 的时间分辨荧光能量转移测定，并且进一步评估了 11 个类似物在无性 3D7（氯喹敏感）寄生虫株中的活性。建立了与环 A 和环 B 的 SAR 关系。这些数据以及对从现场患者中收集的寄生虫活性的分析表明，TCMDC-135051 是一种很有前途的先导化合物，可用于开发针对 CLK3 的新型作用机制的新型抗疟药物。
