Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis
Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis
复制标题
发现针对 RIPK1 激酶活性的有效坏死性凋亡抑制剂，用于治疗炎症性疾病和癌症转移
DOI：
10.1038/s41419-019-1735-6
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发表时间：
2019-06-24
影响因子：
9
通讯作者：
He, Sudan
中科院分区：
文献类型：
--
作者：
Hou, Jue;Ju, Jie;He, Sudan
坏死性凋亡是一种受受体相互作用激酶1（RIPK 1或RIP 1）、RIPK 3（RIP 3）和假激酶混合谱系激酶结构域样蛋白（MLKL）控制的调节性坏死形式。越来越多的证据表明，坏死性凋亡与包括炎性疾病、神经退行性疾病和癌症转移在内的病理学密切相关。在此，我们发现小分子PK 6及其衍生物作为一类新的坏死性凋亡抑制剂，直接阻断RIPK 1的激酶活性。PK 6的优化导致PK 68，其具有改善的抑制RIPK 1依赖性坏死性凋亡的功效，在人和小鼠细胞中的EC 50约为14-22 nM。在坏死性凋亡刺激后，PK 68有效地阻断RIPK 1、RIPK 3和MLKL的细胞活化。PK 68对RIPK 1激酶活性的抑制显示出合理的选择性和有利的药代动力学性质。重要的是，PK 68在体内对TNF-α诱导的全身炎症反应综合征提供了强有力的保护。此外，PK 68的预处理显著抑制小鼠中黑素瘤细胞和肺癌细胞的转移。总之，我们的研究表明，PK 68是RIPK 1的有效和选择性抑制剂，也突出了其在治疗炎症性疾病和癌症转移中的巨大潜力。
Necroptosis is a form of regulated necrosis controlled by receptor-interacting kinase 1 (RIPK1 or RIP1), RIPK3 (RIP3), and pseudokinase mixed lineage kinase domain-like protein (MLKL). Increasing evidence suggests that necroptosis is closely associated with pathologies including inflammatory diseases, neurodegenerative diseases, and cancer metastasis. Herein, we discovered the small-molecule PK6 and its derivatives as a novel class of necroptosis inhibitors that directly block the kinase activity of RIPK1. Optimization of PK6 led to PK68, which has improved efficacy for the inhibition of RIPK1-dependent necroptosis, with an EC50of around 14–22 nM in human and mouse cells. PK68 efficiently blocks cellular activation of RIPK1, RIPK3, and MLKL upon necroptosis stimuli. PK68 displays reasonable selectivity for inhibition of RIPK1 kinase activity and favorable pharmacokinetic properties. Importantly, PK68 provides strong protection against TNF-α-induced systemic inflammatory response syndrome in vivo. Moreover, pre-treatment of PK68 significantly represses metastasis of both melanoma cells and lung carcinoma cells in mice. Together, our study demonstrates that PK68 is a potent and selective inhibitor of RIPK1 and also highlights its great potential for use in the treatment of inflammatory disorders and cancer metastasis.