The ALBORADA Drug Discovery Institute, University of Cambridge, Island Research Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0AH, U.K.
UK Dementia Research Institute, University of Cambridge, Island Research Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0AH, U.K.
J Med Chem. 2022 Feb 24;65(4):3359-3370. doi: 10.1021/acs.jmedchem.1c01819. Epub 2022 Feb 11.
Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are emerging as attractive therapeutic targets in diseases, such as cancer, immunological disorders, and neurodegeneration, owing to their central role in regulating cell signaling pathways that are either dysfunctional or can be modulated to promote cell survival. Different modes of binding may enhance inhibitor selectivity and reduce off-target effects in cells. Here, we describe efforts to improve the physicochemical properties of the selective PI5P4Kγ inhibitor, NIH-12848 (). These improvements enabled the demonstration that this chemotype engages PI5P4Kγ in intact cells and that compounds from this series do not inhibit PI5P4Kα or PI5P4Kβ. Furthermore, the first X-ray structure of PI5P4Kγ bound to an inhibitor has been determined with this chemotype, confirming an allosteric binding mode. An exemplar from this chemical series adopted two distinct modes of inhibition, including through binding to a putative lipid interaction site which is 18 Å from the ATP pocket.
磷脂酰肌醇 5-磷酸 4-激酶（PI5P4Ks）在癌症、免疫紊乱和神经退行性疾病等疾病中作为有吸引力的治疗靶点出现，这是由于它们在调节细胞信号通路方面的核心作用，这些信号通路要么功能失调，要么可以调节以促进细胞存活。不同的结合模式可以提高抑制剂的选择性，并减少细胞中的脱靶效应。在这里，我们描述了努力改善选择性 PI5P4Kγ 抑制剂 NIH-12848 () 的物理化学性质。这些改进使我们能够证明这种化学型在完整细胞中与 PI5P4Kγ 结合，并且该系列化合物不抑制 PI5P4Kα 或 PI5P4Kβ。此外，还首次确定了这种化学型与抑制剂结合的 PI5P4Kγ 的 X 射线结构，证实了变构结合模式。该化学系列的一个范例采用了两种不同的抑制模式，包括通过与假定的脂质相互作用位点结合，该位点距离 ATP 结合口袋 18 Å。
Zotero 插件