Design and synthesis of Grp94 selective inhibitors based on Phe199 induced fit mechanism and their anti-inflammatory effects
Design and synthesis of Grp94 selective inhibitors based on Phe199 induced fit mechanism and their anti-inflammatory effects
复制标题
基于Phe199诱导契合机制的Grp94选择性抑制剂的设计与合成及其抗炎作用
DOI：
10.1016/j.ejmech.2021.113604
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发表时间：
2021
影响因子：
6.7
通讯作者：
Xiao-Li Xu
中科院分区：
文献类型：
--
作者：
Shicheng Xu;An-ping Guo;Nan-Nan Chen;Wei Dai;Huan-aoyu Yang;Wenqin Xie;Mengjie Wang;Qidong You;Xiao-Li Xu
葡萄糖调节蛋白 94 (Grp94) 是热休克蛋白 90 (Hsp90) 家族的成员，与许多人类疾病有关，包括癌症、神经退行性疾病、炎症和传染病。在这里，我们描述了我们基于 Phe199 诱导契合机制设计和开发一系列新的 Grp94 抑制剂的努力。使用含炔基抑制剂作为起点，我们开发了化合物 4，它在基于荧光偏振的测定中显示出对 Grp94 的有效抑制活性。化合物4具有改善的理化性质和合适的药代动力学性质，已进入体内生物活性评价。在葡聚糖硫酸钠 (DSS) 诱导的溃疡性结肠炎 (UC) 小鼠模型中，化合物 4 显示出抗炎特性并降低促炎细胞因子（TNF-α 和 IL-6）的水平。总之，这些发现提供了证据，表明这种方法可能有希望进一步促进 Grp94 药物开发工作。 • 基于Phe199 诱导契合机制，设计并合成了一类新型含炔基衍生物作为Grp94 抑制剂。 • 化合物4 表现出有效的Grp94 抑制活性并改善了理化性质。 • 化合物4 在肝微粒体中稳定并具有合适的PK 特性。 • 化合物4 在溃疡性结肠炎小鼠模型中显示出抗炎作用。
Glucose-regulated protein 94 (Grp94), a member of the Heat shock protein 90 (Hsp90) family, is implicated in many human diseases, including cancer, neurodegeneration, inflammatory, and infectious diseases. Here, we describe our effort to design and develop a new series of Grp94 inhibitors based on Phe199 induced fit mechanism. Using an alkynyl-containing inhibitor as a starting point, we developed compound 4 , which showed potent inhibitory activity toward Grp94 in a fluorescence polarization-based assay. With improved physicochemical properties and suitable pharmacokinetic properties, compound 4 was advanced into in vivo bioactivity evaluation. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 4 showed anti-inflammatory property and reduced the levels of pro-inflammatory cytokines (TNF-α and IL-6). Together, these findings provide evidence that this approach may be promising for further Grp94 drug development efforts. • A novel class of alkynyl-containing derivatives as Grp94 inhibitors were designed and synthesized based on Phe199 induced fit mechanism. • Compound 4 exhibited potent Grp94 inhibitory activity and improved physicochemical properties. • Compound 4 was stable in liver microsomes and had a suitable PK profile. • Compound 4 showed anti-inflammatory effect in a mouse model of ulcerative colitis.