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

• Published in: Bioorganic & medicinal chemistry 2017-12, Vol.25 (24), p.6563-6580
• Main Authors: Fukuda, Tsutomu, Umeki, Teppei, Tokushima, Keiji, Xiang, Gao, Yoshida, Yuki, Ishibashi, Fumito, Oku, Yusuke, Nishiya, Naoyuki, Uehara, Yoshimasa, Iwao, Masatomo
• Format: Article
• Language: English
• Subjects: Dose-Response Relationship, Drug; Drug Design; EGFR T790M/L858R mutant; EGFR tyrosine kinase inhibitors (EGFR-TKI); Heterocyclic Compounds, 4 or More Rings - chemical synthesis; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Lamellarin N; Molecular Docking Simulation; Molecular Structure; Mutation; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Structure-Activity Relationship; Structure-based drug design (SBDD); Water-soluble analogues
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.10.030

[Display omitted] 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.