Design, synthesis, and evaluation of A-ring-modified lamellarin N analogues as noncovalent inhibitors of the EGFR T790M/L858R mutant

Publication date: Available online 24 October 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): 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.

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