Synthesis and characterization of potent RIPK3 inhibitors based on a tricyclic scaffold.
Synthesis and characterization of potent RIPK3 inhibitors based on a tricyclic scaffold.
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DOI：
10.4155/fmc-2021-0196
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发表时间：
2022-02
影响因子：
4.2
通讯作者：
Shuwei Wu;Qing Yang;Yuting Ji;Sheng Tian;Haikuo Ma;Shujing Du;Haohao Lu;S. He;Xiaohu Zhang
中科院分区：
文献类型：
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作者：
Shuwei Wu;Qing Yang;Yuting Ji;Sheng Tian;Haikuo Ma;Shujing Du;Haohao Lu;S. He;Xiaohu Zhang
背景：坏死性上睑下垂是炎症性疾病、退行性疾病和癌症中重要的细胞死亡形式。RIPK3是干预坏死相关疾病的一个有趣的靶点。方法：本文作者在基于结构的药物设计指导下合成了一系列RIPK3抑制剂，并鉴定了化合物37。结果：化合物37能有效地保护人和小鼠细胞免受TNFα、Smac mimic、z-VAD和LPS + z-VAD的坏死刺激，对RIPK3具有较高的亲和力（Kd = 14 nM），但对RIPK3无明显的亲和力，并能抑制RIPK3激酶的功能。重要的是，化合物37在小鼠模型中显著缓解了tnf诱导的全身炎症反应综合征。结论：这些结果支持化合物37作为RIPK3先导物的原型抑制剂。
Background: Necroptosis is an important form of regulated cell death involved in inflammatory diseases, degenerative diseases and cancer. RIPK3 is an interesting target for intervention of necroptosis-associated diseases. Methodology: Herein the authors report the synthesis of a series RIPK3 inhibitors under the guidance of structure-based drug design which leads to the identification of compound 37. Results: Compound 37 potently rescued human and mouse cells from necroptotic stimuli TNFα, Smac mimetic, z-VAD and LPS + z-VAD, displayed high affinity to RIPK3 (Kd = 14 nM) but no observable affinity to RIPK1 and inhibited RIPK3 kinase function. Importantly, compound 37 significantly alleviated TNF-induced systemic inflammatory response syndrome in the mouse model. Conclusion: These results support compound 37 as a prototype RIPK3 inhibitor for lead optimization.