Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors
Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors
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艾伦酰胺作为丙烯酰胺的生物等排体用于靶向共价抑制剂的设计和合成
DOI：
10.1039/c7md00571g
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发表时间：
2018-02-01
期刊：
影响因子：
--
通讯作者：
Zhao, Yujun
中科院分区：
文献类型：
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作者：
Chen, Deheng;Guo, Dexiang;Zhao, Yujun
含丙烯酰胺的药物在治疗癌症方面的成功激发了人们寻找丙烯酰胺生物同工酯的热情。在我们的努力中，我们已经确定了丙烯酰胺基团可以是丙烯酰胺基团的活性生物同质体。在我们的含烯酰胺类化合物的开发中，我们发现最有效的化合物14在低nM范围内抑制T790M/L858R双突变体和野生型EGFR的激酶活性。14对NCI-H1975肺癌细胞的生长也有抑制作用，IC50 = 33 nM，与含丙烯酰胺的奥西替尼相当。western blot分析显示，14对NCI-H1975细胞同时抑制EGFR、AKT和ERK1/2的磷酸化，且呈剂量依赖性。通过测定14与谷胱甘肽形成的共轭加成产物，我们得到了302.5 × 10(-3) min（-1）的反应速率常数，比奥西替尼的反应速率常数高约30倍。综上所述，我们的数据表明，含烯酰胺的化合物通过共价修饰抑制EGFR激酶。我们的研究表明，烯丙酰胺基团可以作为一种替代的亲电战斗部来设计靶向共价抑制剂，这种生物同质体替代在药物化学中具有广泛的应用前景。
The success of acrylamide-containing drugs in treating cancers has spurred a passion to search for acrylamide bioisosteres. In our endeavour, we have identified that an allenamide group can be a reactive bioisostere of the acrylamide group. In our development of allenamide-containing compounds, we found that the most potent compound, 14, inhibited the kinase activities of both T790M/L858R double mutant and wild type EGFR in a low nM range. 14 also inhibited the growth of NCI-H1975 lung cancer cells at IC50 = 33 nM, which is comparable to that of acrylamide-containing osimertinib. The western blot analysis showed that the phosphorylation of EGFR, AKT, and ERK1/2 was simultaneously inhibited in a dose-dependent manner when NCI-H1975 cells were treated with 14. By measuring the conjugate addition product formed by 14 and GSH, we obtained a reaction rate constant of 302.5 x 10(-3) min(-1), which is about 30-fold higher than that of osimertinib. Taken together, our data suggest that the allenamide-containing compounds inhibited EGFR kinases through covalent modifications. Our study indicates that the allenamide group could serve as an alternative electrophilic warhead in the design of targeted covalent inhibitors, and this bioisostere replacement may have broad applications in medicinal chemistry.