School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China.
School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China.
Bioorg Med Chem. 2023 Aug 15;91:117385. doi: 10.1016/j.bmc.2023.117385. Epub 2023 Jun 20.
Receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis is believed to have a significant role in contributing to inflammatory diseases. Inhibiting RIPK1 has shown promise in effectively alleviating the inflammation process. In our current study, we employed scaffold hopping to develop a series of novel benzoxazepinone derivatives. Among these derivatives, compound o1 displayed the most potent antinecroptosis activity (EC50=16.17±1.878nM) in cellular assays and exhibited the strongest binding affinity to the target site. Molecular docking analyses further elucidated the mechanism of action of o1, revealing its ability to fully occupy the protein pocket and form hydrogen bonds with the amino acid residue Asp156. Our findings highlight that o1 specifically inhibits necroptosis, rather than apoptosis, by impeding the RIPK1/Receptor-interacting protein kinase 3 (RIPK3)/mixed-lineage kinase domain-like (MLKL) pathway's phosphorylation, triggered by TNFα, Smac mimetic, and z-VAD (TSZ). Additionally, o1 demonstrated dose-dependent improvements in the survival rate of mice with Systemic Inflammatory Response Syndrome (SIRS), surpassing the protective effect observed with GSK'772.
受体相互作用蛋白激酶 1（RIPK1）介导的坏死性凋亡被认为在炎症性疾病中起重要作用。抑制 RIPK1 已被证明能有效缓解炎症过程。在我们目前的研究中，我们采用了支架跳跃的方法来开发一系列新型苯并恶嗪酮衍生物。在这些衍生物中，化合物 o1 在细胞实验中表现出最强的抗坏死性凋亡活性（EC50=16.17±1.878nM），并显示出与靶位最强的结合亲和力。分子对接分析进一步阐明了 o1 的作用机制，揭示了它能够完全占据蛋白质口袋并与天冬氨酸残基 Asp156 形成氢键。我们的研究结果表明，o1 通过阻止 TNFα、Smac 模拟物和 z-VAD（TSZ）触发的 RIPK1/受体相互作用蛋白激酶 3（RIPK3）/混合谱系激酶结构域样（MLKL）途径的磷酸化，特异性抑制坏死性凋亡，而不是凋亡。此外，o1 还表现出对全身炎症反应综合征（SIRS）小鼠存活率的剂量依赖性改善，超过了 GSK'772 的保护作用。
