A环修饰的片螺素N类似物作为表皮生长因子受体T790M/L858R突变体非共价抑制剂的设计、合成与评价
Design, synthesis, and evaluation of A-ring-modified lamellarin N analogues as noncovalent inhibitors of the EGFR T790M/L858R mutant.
作者信息
Fukuda Tsutomu, Umeki Teppei, Tokushima Keiji, Xiang Gao, Yoshida Yuki, Ishibashi Fumito, Oku Yusuke, Nishiya Naoyuki, Uehara Yoshimasa, Iwao Masatomo
机构信息
Division of Chemistry and Materials Science, Graduate School of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Division of Marine Life Science and Biochemistry, Graduate School of Fisheries and Environmental Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
出版信息
Bioorg Med Chem. 2017 Dec 15;25(24):6563-6580. doi: 10.1016/j.bmc.2017.10.030. Epub 2017 Oct 24.
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 [IC (WT) = 31.8 nM; IC (T790M/L858R) = 8.9 nM]. The effects of A-ring-substituents on activity were rationalized by docking studies.
设计、合成并评估了一系列A环修饰的片螺素N类似物，作为表皮生长因子受体（EGFR）T790M/L858R突变体的潜在非共价抑制剂，该突变体是耐药性非小细胞肺癌的一个致病因素。几种连接水溶性铵或胍的类似物表现出良好的激酶抑制活性。最有前景的类似物14f对T790M/L858R突变体显示出优异的抑制谱[IC（野生型）=31.8 nM；IC（T790M/L858R）=8.9 nM]。通过对接研究阐明了A环取代基对活性的影响。
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