2. Academic Validation
  3. Synthesis and evaluation of azalamellarin N and its A-ring-modified analogues as non-covalent inhibitors of the EGFR T790M/L858R mutant

Synthesis and evaluation of azalamellarin N and its A-ring-modified analogues as non-covalent inhibitors of the EGFR T790M/L858R mutant

  • Bioorg Med Chem. 2021 Mar 15:34:116039. doi: 10.1016/j.bmc.2021.116039.
Tsutomu Fukuda 1,  Mizuho Anzai 2,  Akane Nakahara 2,  Kentaro Yamashita 2,  Kazuaki Matsukura 3,  Fumito Ishibashi 3,  Yusuke Oku 4,  Naoyuki Nishiya 4,  Yoshimasa Uehara 4,  Masatomo Iwao 2
Affiliations

Affiliations

  • 1 Environmental Protection Center, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. Electronic address: t-fukuda@nagasaki-u.ac.jp.
  • 2 Division of Chemistry and Materials Science, Graduate School of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
  • 3 Division of Marine Life Science and Biochemistry, Graduate School of Fisheries and Environmental Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
  • 4 Department of Integrated Information for Pharmaceutical Sciences, Iwate Medical University School of Pharmacy, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan.
PMID: 33556869 DOI: 10.1016/j.bmc.2021.116039
Abstract

Azalamellarin N, a synthetic lactam congener of the marine natural product lamellarin N, and its A-ring-modified analogues were synthesized and evaluated as potent and non-covalent inhibitors of the drug-resistant epidermal growth factor receptor T790M/L858R mutant. An in vitro tyrosine kinase assay indicated that the inhibitory activities of the synthetic azalamellarin analogues were higher than those of the corresponding lamellarins. The azalamellarin analogue bearing two 3-(dimethylamino)propoxy groups at C20- and C21-positions exhibited the highest activity and selectivity against the mutant kinase [IC50 (T790M/L858R) = 1.7 nM; IC50 (WT) = 4.6 nM]. The inhibitory activity was attributed to the hydrogen bonding interaction between the lactam NH group of the B-ring and carbonyl group of a methionine residue.

Keywords

A-ring-modified azalamellarin analogues; Azalamellarin N; EGFR T790M/L858R mutant; EGFR tyrosine kinase inhibitors (EGFR-TKIs).

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