Ring closure strategy leads to potent RIPK3 inhibitors.
Ring closure strategy leads to potent RIPK3 inhibitors.
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DOI：
10.1016/j.ejmech.2021.113327
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发表时间：
2021-03
影响因子：
6.7
通讯作者：
Shuwei Wu;Chen Xu;Kaijiang Xia;Yu Lin;Sheng Tian;Haikuo Ma;Yuting Ji;Fang Zhu;S. He;Xiaohu Zhang
中科院分区：
文献类型：
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作者：
Shuwei Wu;Chen Xu;Kaijiang Xia;Yu Lin;Sheng Tian;Haikuo Ma;Yuting Ji;Fang Zhu;S. He;Xiaohu Zhang
坏死性凋亡是一种不依赖于半胱天冬酶的调节性坏死细胞死亡形式。受体相互作用蛋白激酶3（RIPK 3）已被确定为坏死性凋亡的关键调节因子，并已被提出作为治疗坏死性凋亡相关疾病的潜在治疗靶点。在这份报告中，我们描述了一系列新的RIPK 3抑制剂的设计，合成和评价。先导化合物38对TNFα、Smac模拟物和z-VAD（TSZ）诱导的HT-29细胞死亡具有较强的阻断作用（EC_（50）= 0.42 μM）。机理研究表明，化合物38以高亲和力（Kd= 7.1 nM）结合RIPK 3，并在ADP-Glo功能测定中抑制RIPK 3激酶活性。此外，化合物38对另一种坏死性凋亡调节剂RIPK 1（Kd= 6000 nM）表现出良好的选择性。此外，化合物38表现出优异的体外安全性特征，具有最小的对hERG同工酶和hERG钾通道的抑制。最后，化合物38有效地阻断了TNFα诱导的全身炎症反应综合征模型中小鼠的体温过低和死亡。
Necroptosis is a form of regulated necrotic cell death that is independent of caspases. Receptor-interacting protein kinase 3 (RIPK3) has been identified as a key regulator for necroptosis, and has been proposed as a potential therapeutic target for the treatment of diseases associated with necroptosis. In this report, we describe the design, synthesis, and evaluation of a series of novel RIPK3 inhibitors. The lead compound38exhibited potent activity (EC50= 0.42 μM) in blocking TNFα, Smac mimetic and z-VAD (TSZ) induced cell death in HT-29 cells. Mechanistic studies showed that compound38bound to RIPK3 with high affinity (Kd= 7.1 nM), and inhibited RIPK3 kinase activity in a ADP-Glo functional assay. In addition, compound38displayed good selectivity over another necroptosis regulator RIPK1 (Kd= 6000 nM). Furthermore, compound38demonstrated excellent in vitro safety profiles with minimal inhibition of CYP isozymes and hERG potassium channel. Lastly, compound38efficiently blocked hypothermia and death in mice in the TNFα-induced systemic inflammatory response syndrome model.