Discovery of boron-conjugated 4-anilinoquinazoline as a prolonged inhibitor of EGFR tyrosine kinase.
Boron-conjugated 4-anilinoquinazolines were designed and synthesized as inhibitors of EGFR tyrosine kinase with possible covalent bond interactions between the boron atom and the nucleophilic groups of the EGFR kinase domain. Among the compounds synthesized, compounds 6c, 7b, and 7d reduced the EGF-mediated phosphorylation of EGFR tyrosine kinase and its downstream kinases including ERK and Akt in A431 cells. The cell growth was inhibited by these compounds through arrest of G1 cell cycle, which induced apoptosis. A time-dependent in vitro preincubation assay demonstrated the irreversible inhibition of compound 7d against EGFR tyrosine kinase. Quantum mechanical docking simulation revealed that the boronic acid moiety of compound 7d formed a covalent B-O bond with Asp800 in addition to hydrogen bonds with Asp800 and Cys797, which may cause the prolonged inhibition of compound 7d toward EGFR tyrosine kinase.
Ban
Hyun Seung
HS
Department of Chemistry, Faculty of Science, Gakushuin University, Tokyo, 171-8588, Japan.
Usui
Taikou
T
Nabeyama
Wataru
W
Morita
Hidetoshi
H
Fukuzawa
Kaori
K
Nakamura
Hiroyuki
H
D017209:Apoptosis / Q000187:drug effects; D001896:Boron Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011789:Quantum Theory; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013816:Thermodynamics; D013997:Time Factors
D001896:Boron Compounds; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors