Inositol Signaling Group, Signal Transduction Laboratory , National Institute of Environmental Health Sciences , Research Triangle Park , North Carolina 27709 , United States.
Center for Integrative Chemical Biology and Drug Discovery, 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.
J Med Chem. 2019 Feb 14;62(3):1443-1454. doi: 10.1021/acs.jmedchem.8b01593. Epub 2019 Jan 25.
Dietary flavonoids inhibit certain protein kinases and phospholipid kinases by competing for their ATP-binding sites. These nucleotide pockets have structural elements that are well-conserved in two human small-molecule kinases, inositol hexakisphosphate kinase (IP6K) and inositol polyphosphate multikinase (IPMK), which synthesize multifunctional inositol phosphate cell signals. Herein, we demonstrate that both kinases are inhibited by quercetin and 16 related flavonoids; IP6K is the preferred target. Relative inhibitory activities were rationalized by X-ray analysis of kinase/flavonoid crystal structures; this detailed structure-activity analysis revealed hydrophobic and polar ligand/protein interactions, the degree of flexibility of key amino acid side chains, and the importance of water molecules. The seven most potent IP6K inhibitors were incubated with intact HCT116 cells at concentrations of 2.5 μM; diosmetin was the most selective and effective IP6K inhibitor (>70% reduction in activity). Our data can instruct on pharmacophore properties to assist the future development of inositol phosphate kinase inhibitors. Finally, we propose that dietary flavonoids may inhibit IP6K activity in cells that line the gastrointestinal tract.
饮食中的类黄酮通过与 ATP 结合位点竞争来抑制某些蛋白激酶和磷脂酶激酶。这些核苷酸结合口袋在两种人类小分子激酶中具有高度保守的结构元素，即肌醇六磷酸激酶（IP6K）和肌醇多磷酸激酶（IPMK），它们合成多功能肌醇磷酸细胞信号。在此，我们证明这两种激酶均被槲皮素和 16 种相关类黄酮抑制；IP6K 是首选靶标。通过激酶/类黄酮晶体结构的 X 射线分析来合理化相对抑制活性；这种详细的结构-活性分析揭示了疏水性和极性配体/蛋白质相互作用、关键氨基酸侧链的柔韧性以及水分子的重要性。将七种最有效的 IP6K 抑制剂以 2.5μM 的浓度与完整的 HCT116 细胞孵育；染料木素是最具选择性和有效的 IP6K 抑制剂（活性降低超过 70%）。我们的数据可以指导药效团特性，以协助未来开发肌醇磷酸激酶抑制剂。最后，我们提出饮食中的类黄酮可能会抑制胃肠道细胞中的 IP6K 活性。
