J Med Chem. 2018 Sep 27;61(18):8061-8077. doi: 10.1021/acs.jmedchem.8b00329. Epub 2018 Jun 4.
Advances in the genetics, function, and stage-specificity of Plasmodium kinases has driven robust efforts to identify targets for the design of antimalarial therapies. Reverse genomics following phenotypic screening against Plasmodia or related parasites has uncovered vulnerable kinase targets including PI4K, PKG, and GSK-3, an approach bolstered by access to human disease-directed kinase libraries. Alternatively, screening compound libraries against Plasmodium kinases has successfully led to inhibitors with antiplasmodial activity. As with other therapeutic areas, optimizing compound ADMET and PK properties in parallel with target inhibitory potency and whole cell activity becomes paramount toward advancing compounds as clinical candidates. These and other considerations will be discussed in the context of progress achieved toward deriving important, novel mode-of-action kinase-inhibiting antimalarial medicines.
疟原虫激酶的遗传学、功能和阶段特异性方面的进展推动了人们积极努力地寻找针对抗疟疗法的设计靶点。针对疟原虫或相关寄生虫进行表型筛选后进行反向基因组学研究，揭示了易受攻击的激酶靶点，包括 PI4K、PKG 和 GSK-3，这种方法得益于获得了针对人类疾病的激酶文库。或者，针对疟原虫激酶筛选化合物文库也成功地得到了具有抗疟活性的抑制剂。与其他治疗领域一样，在优化化合物的 ADMET 和 PK 特性的同时，提高靶标抑制能力和全细胞活性，对于将化合物推进为临床候选药物至关重要。这些以及其他方面的考虑将在探讨取得重要的新型作用机制的激酶抑制剂抗疟药物的进展的背景下进行讨论。
