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

Abstract

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.

• Authors: Tsutomu Fukuda, Teppei Umeki, Keiji Tokushima, Gao Xiang, Yuki Yoshida, Fumito Ishibashi, Yusuke Oku, Naoyuki Nishiya, Yoshimasa Uehara, Masatomo Iwao
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 25 Issue 24 Pg. 6563-6580 (12 15 2017) ISSN: 1464-3391 [Electronic] England
• PMID: 29133033 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Heterocyclic Compounds, 4 or More Rings
• Protein Kinase Inhibitors
• lamellarin N
• EGFR protein, human
• ErbB Receptors

Topics

• Dose-Response Relationship, Drug
• Drug Design
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Heterocyclic Compounds, 4 or More Rings (chemical synthesis, chemistry, pharmacology)
• Humans
• Molecular Docking Simulation
• Molecular Structure
• Mutation
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship