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

Tsutomu Fukuda; Teppei Umeki; Keiji Tokushima; Gao Xiang; Yuki Yoshida; Fumito Ishibashi; Yusuke Oku; Naoyuki Nishiya; Yoshimasa Uehara; Masatomo Iwao

doi:10.1016/j.bmc.2017.10.030

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

Bioorg Med Chem. 2017 Dec 15;25(24):6563-6580. doi: 10.1016/j.bmc.2017.10.030. Epub 2017 Oct 24.

Authors

Affiliations

¹ Division of Chemistry and Materials Science, Graduate School of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
² Division of Marine Life Science and Biochemistry, Graduate School of Fisheries and Environmental Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
³ Department of Integrated Information for Pharmaceutical Sciences, Iwate Medical University School of Pharmacy, 2-1-1 Nishitokuta, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan.
⁴ Division of Chemistry and Materials Science, Graduate School of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. Electronic address: iwao@nagasaki-u.ac.jp.

PMID: 29133033
DOI: 10.1016/j.bmc.2017.10.030

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.

Keywords: EGFR T790M/L858R mutant; EGFR tyrosine kinase inhibitors (EGFR-TKI); Lamellarin N; Structure-based drug design (SBDD); Water-soluble analogues.

MeSH terms

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

Substances

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