Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2017-10-24 , DOI: 10.1016/j.bmc.2017.10.030 Tsutomu Fukuda , Teppei Umeki , Keiji Tokushima , Gao Xiang , Yuki Yoshida , Fumito Ishibashi , Yusuke Oku , Naoyuki Nishiya , Yoshimasa Uehara , Masatomo Iwao
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.
中文翻译:
设计,合成和评估A环修饰的lamellarin N类似物作为EGFR T790M / L858R突变体的非共价抑制剂
设计,合成和评估了一系列A环修饰的lamellarin N类似物,作为EGFR T790M / L858R突变体的潜在非共价抑制剂,EGFR T790M / L858R突变体是耐药性非小细胞肺癌的致病因素。几种水溶性铵盐或胍盐系的类似物表现出良好的激酶抑制活性。最有前途的类似物14f对T790M / L858R突变体表现出优异的抑制作用[IC 50(WT)= 31.8 nM; IC 50(T790M / L858R)= 8.9 nM]。通过对接研究合理化了A环取代基对活性的影响。