Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
Department of Biological Sciences, KAIST, Daejeon 34141, Korea.
Mol Cells. 2020 Mar 31;43(3):222-227. doi: 10.14348/molcells.2020.0051.
Inositol polyphosphate multikinase (IPMK) is required for the biosynthesis of inositol phosphates (IPs) through the phosphorylation of multiple IP metabolites such as IP3 and IP4. The biological significance of IPMK's catalytic actions to regulate cellular signaling events such as growth and metabolism has been studied extensively. However, pharmacological reagents that inhibit IPMK have not yet been identified. We employed a structure-based virtual screening of publicly available U.S. Food and Drug Administration-approved drugs and chemicals that identified the antidepressant, vilazodone, as an IPMK inhibitor. Docking simulations and pharmacophore analyses showed that vilazodone has a higher affinity for the ATP-binding catalytic region of IPMK than ATP and we validated that vilazodone inhibits IPMK's IP kinase activities in vitro . The incubation of vilazodone with NIH3T3-L1 fibroblasts reduced cellular levels of IP5 and other highly phosphorylated IPs without influencing IP4 levels. We further found decreased Akt phosphorylation in vilazodone-treated HCT116 cancer cells. These data clearly indicate selective cellular actions of vilazodone against IPMK-dependent catalytic steps in IP metabolism and Akt activation. Collectively, our data demonstrate vilazodone as a method to inhibit cellular IPMK, providing a valuable pharmacological agent to study and target the biological and pathological processes governed by IPMK.
肌醇多磷酸激酶（IPMK）通过磷酸化 IP3 和 IP4 等多种 IP 代谢物，参与肌醇磷酸盐（IPs）的生物合成。IPMK 的催化作用对于调节细胞信号事件，如生长和代谢的生物学意义已经得到了广泛的研究。然而，尚未鉴定出抑制 IPMK 的药理学试剂。我们采用基于结构的虚拟筛选，对公开的美国食品和药物管理局批准的药物和化学物质进行筛选，发现抗抑郁药维拉佐酮是一种 IPMK 抑制剂。对接模拟和药效团分析表明，维拉佐酮与 IPMK 的 ATP 结合催化区域的亲和力高于 ATP，我们验证了维拉佐酮在体外抑制 IPMK 的 IP 激酶活性。维拉佐酮与 NIH3T3-L1 成纤维细胞孵育会降低细胞内 IP5 和其他高度磷酸化的 IP 水平，但不影响 IP4 水平。我们还发现，在维拉佐酮处理的 HCT116 癌细胞中 Akt 磷酸化减少。这些数据清楚地表明，维拉佐酮对 IPMK 依赖性催化步骤和 Akt 激活具有选择性的细胞作用。总之，我们的数据表明维拉佐酮可抑制细胞内的 IPMK，为研究和靶向 IPMK 调控的生物学和病理学过程提供了有价值的药理学工具。
