Design, synthesis, and evaluation of A-ring-modified lamellarin N analogues as noncovalent inhibitors of the EGFR T790M/L858R mutant
Design, synthesis, and evaluation of A-ring-modified lamellarin N analogues as noncovalent inhibitors of the EGFR T790M/L858R mutant
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DOI：
10.1016/j.bmc.2017.10.030
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发表时间：
2017-12-15
影响因子：
3.5
通讯作者：
Iwao, Masatomo
中科院分区：
文献类型：
--
作者：
Fukuda, Tsutomu;Umeki, Teppei;Iwao, Masatomo
设计、合成了一系列A环修饰的片螺素N类似物，并评估其作为EGFR T790 M/L 858 R突变体的潜在非共价抑制剂，EGFR T790 M/L 858 R突变体是耐药非小细胞肺癌的致病因素。几种水溶性的铵或胍类似物具有良好的激酶抑制活性。最有希望的类似物14 f对T790 M/L 858 R突变体显示出优异的抑制特性[IC 50（WT）= 31.8 nM; IC 50（T790 M/L 858 R）= 8.9 nM]。通过对接研究，合理化了A环取代基对活性的影响。(C)2017爱思唯尔有限公司版权所有。
A series of A-ring-modified lamellarin N analogues were designed, synthesized, and evaluated as potential noncovalent inhibitors of the EGFR T790M/L858R mutant, a causal factor in the drug-resistant non-small cell lung cancer. Several water-soluble ammonium- or guanidinium-tethered analogues exhibited good kinase inhibitory activities. The most promising analogue, 14f, displayed an excellent inhibitory profile against the T790M/L858R mutant [IC50 (WT) = 31.8 nM; IC50 (T790M/L858R) = 8.9 nM]. The effects of A-ring-substituents on activity were rationalized by docking studies. (C) 2017 Elsevier Ltd. All rights reserved.