Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Department of Chemistry, Duke University, 124 Science Drive, Durham, North Carolina 27708, United States.
J Med Chem. 2022 Oct 13;65(19):13172-13197. doi: 10.1021/acs.jmedchem.2c00996. Epub 2022 Sep 27.
Essential plasmodial kinases GSK3 and PK6 are considered novel drug targets to combat rising resistance to traditional antimalarial therapy. Herein, we report the discovery of as a dual GSK3/PK6 inhibitor active against blood stage 3D7 parasites. To establish structure-activity relationships for PK6 and GSK3, 52 analogues were synthesized and assessed for the inhibition of GSK3 and PK6, with potent inhibitors further assessed for activity against blood and liver stage parasites. This culminated in the discovery of dual GSK3/PK6 inhibitors (GSK3/PK6 IC = 172/11 nM) and (GSK3/PK6 IC = 97/8 nM) with antiplasmodial activity ( 3D7 EC = 552 ± 37 nM and 3D7 EC = 1400 ± 13 nM). However, both compounds exhibited significant promiscuity when tested in a panel of human kinase targets. Our results demonstrate that dual PK6/GSK3 inhibitors with antiplasmodial activity can be identified and can set the stage for further optimization efforts.
疟原虫必需激酶 GSK3 和 PK6 被认为是对抗传统抗疟疗法耐药性上升的新型药物靶点。在此，我们报告了作为一种双重 GSK3/PK6 抑制剂的发现，该抑制剂对 3D7 期血虫具有活性。为了建立 PK6 和 GSK3 的构效关系，合成了 52 个类似物，并评估了它们对 GSK3 和 PK6 的抑制作用，具有较强抑制作用的进一步评估了对血期和肝期寄生虫的活性。这最终发现了双重 GSK3/PK6 抑制剂 （GSK3/PK6 IC = 172/11 nM）和 （GSK3/PK6 IC = 97/8 nM），具有抗疟原虫活性（ 3D7 EC = 552 ± 37 nM 和 3D7 EC = 1400 ± 13 nM）。然而，当在一组人类激酶靶标中进行测试时，这两种化合物都表现出显著的混杂性。我们的结果表明，可以识别出具有抗疟原虫活性的双重 PK6/GSK3 抑制剂，并为进一步的优化努力奠定基础。
