State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, PR China.
Department of Neurology, Chongzhou People's Hospital, Chengdu, 611230, PR China.
Eur J Med Chem. 2020 Jul 1;197:112314. doi: 10.1016/j.ejmech.2020.112314. Epub 2020 Apr 15.
Myocardial infarction (MI) injury is a highly lethal syndrome that has, until recently, suffered from a lack of clinically efficient targeted therapeutics. The cardiac troponin I interacting kinase (TNNI3K) exacerbates ischemia-reperfusion (IR) injury via oxidative stress, thereby promoting cardiomyocyte death. In this current study, we designed and synthesized 35 novel TNNI3K inhibitors with a pyrido[4,5]thieno[2,3-d] pyrimidine scaffold. In vitro results indicated that some of the inhibitors exhibited sub-micromolar TNNI3K inhibitory capacity and good kinase selectivity, as well as cytoprotective activity, in an oxygen-glucose deprivation (OGD) injury cardiomyocyte model. Furthermore, investigation of the mechanism of the representative derivative compound 6o suggested it suppresses pyroptosis and apoptosis in cardiomyocytes by interfering with p38MAPK activation, which was further confirmed in a murine myocardial infarction injury model. In vivo results indicate that compound 6o can markedly reduce myocardial infarction size and alleviate cardiac tissue damage in rats. In brief, our results provide the basis for further development of novel TNNI3K inhibitors for targeted MI therapy.
心肌梗死 (MI) 损伤是一种高度致命的综合征，直到最近，它一直缺乏临床有效的靶向治疗方法。心肌肌钙蛋白 I 相互作用激酶 (TNNI3K) 通过氧化应激加剧缺血再灌注 (IR) 损伤，从而促进心肌细胞死亡。在本研究中，我们设计并合成了 35 种具有吡啶并[4,5]噻吩并[2,3-d]嘧啶骨架的新型 TNNI3K 抑制剂。体外结果表明，一些抑制剂在氧葡萄糖剥夺 (OGD) 损伤心肌细胞模型中表现出亚微摩尔 TNNI3K 抑制能力和良好的激酶选择性以及细胞保护活性。此外，对代表性衍生物化合物 6o 的机制研究表明，它通过干扰 p38MAPK 激活来抑制心肌细胞中的细胞焦亡和细胞凋亡，这在小鼠心肌梗死损伤模型中得到了进一步证实。体内结果表明，化合物 6o 可显著减少大鼠心肌梗死面积并减轻心脏组织损伤。总之，我们的研究结果为进一步开发用于靶向 MI 治疗的新型 TNNI3K 抑制剂提供了依据。
