Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors.
Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors.
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DOI：
10.1016/j.chembiol.2015.07.017
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发表时间：
2015-09-17
影响因子：
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通讯作者：
Bullock AN
中科院分区：
文献类型：
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作者：
Canning P;Ruan Q;Schwerd T;Hrdinka M;Maki JL;Saleh D;Suebsuwong C;Ray S;Brennan PE;Cuny GD;Uhlig HH;Gyrd-Hansen M;Degterev A;Bullock AN
RIPK 2介导来自细菌传感器NOD 1和NOD 2的促炎信号传导，并且是自身免疫性和炎性疾病的新兴治疗靶点。我们观察到，细胞RIPK 2可以有效地抑制II型抑制剂，取代激酶激活段，而ATP竞争性I型抑制效果不佳。最有效的RIPK 2抑制剂是美国食品和药物管理局批准的药物ponatinib和regorafenib。它们的作用机制不依赖于NOD 2相互作用，并涉及下游激酶活化的丧失，如缺乏RIPK 2自磷酸化所证明的。值得注意的是，这些分子还阻断了RIPK 2泛素化，从而阻断了炎性核因子κB信号传导。在单核细胞中，抑制剂选择性阻断NOD依赖性肿瘤坏死因子的产生，而不影响脂多糖依赖性途径。我们还确定了与泊那替尼结合的RIPK 2的第一个晶体结构，并确定了抑制剂形成的变构位点。这些结果突出了II型抑制剂治疗RIPK 2激活适应症以及炎症相关癌症的潜力。发现II型激酶抑制剂对RIPK 2抑制高度有效RIPK 2自磷酸化和泛素化被FDA批准的药物阻断RIPK 2晶体结构揭示了用于改善药物选择性的变构口袋NOD介导的炎症信号传导被减弱而不影响TLR Canning et al.报告了不同激酶RIPK 2的结构，并描述了FDA批准的药物泊那替尼和瑞格非尼对其的抑制作用。这些抑制剂阻止NOD 2刺激后RIPK 2的自磷酸化和泛素化，并阻断下游NF-κB活化和炎症信号传导。
RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers. Discovery of type II kinase inhibitors as highly efficacious for RIPK2 inhibition RIPK2 autophosphorylation and ubiquitination are blocked by FDA-approved drugs RIPK2 crystal structure reveals an allosteric pocket for improving drug selectivity NOD-mediated inflammatory signaling is attenuated without affecting TLRs Canning et al. report the structure of the diverse kinase RIPK2 and characterize its inhibition by the FDA-approved drugs ponatinib and regorafenib. The inhibitors prevent the autophosphorylation and ubiquitination of RIPK2 upon NOD2 stimulation, and block downstream NF-κB activation and inflammatory signaling.