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

• Fukuda, Tsutomu

• Umeki, Teppei

• Tokushima, Keiji

• Xiang, Gao

• Yoshida, Yuki

• Ishibashi, Fumito

• Oku, Yusuke

• Nishiya, Naoyuki

• Uehara, Yoshimasa

• Iwao, Masatomo

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.

Bioorganic & Medicinal Chemistry, 25(24), pp.6563-6580; 2017

Journal

• Bioorganic & Medicinal Chemistry

  Bioorganic & Medicinal Chemistry 25 (24), 6563-6580, 2017-12-15

  Elsevier Ltd.

Keywords

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

Details

• CRID: 1050850247217341696
• NII Article ID: 120006987775
• ISSN: 09680896
• DOI: 10.1016/j.bmc.2017.10.030
• HANDLE: 10069/38936
• Web Site: https://nagasaki-u.repo.nii.ac.jp/records/1663
• Web Site: https://api.elsevier.com/content/article/PII:S0968089617318643?httpAccept=text/xml
• Web Site: https://api.elsevier.com/content/article/PII:S0968089617318643?httpAccept=text/plain
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN