Design and Evaluation of Potent EGFR Inhibitors through the Incorporation of Macrocyclic Polyamine Moieties into the 4‑Anilinoquinazoline Scaffold

Adenosine
triphosphate (ATP)-competitive inhibitors of the epidermal
growth factor receptor (EGFR) have provided a significant improvement
in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately,
some marketed drugs affect a transient beneficial response in EGFR
mutant NSCLC patients. We reported a series of potential EGFR inhibitors
through incorporation of macrocyclic polyamine into 4-anilinoquinazoline
scaffold. It is expected that anilinoquinazoline part effectively
bind to EGFR domain, while ATP molecules are captured by a macrocyclic
polyamine moiety. In vitro experiments exhibited
that most of tested compounds suppressed tumor cell proliferation
more strongly than Gefitinib and Lapatinib (dual inhibitor of EGFR/HER2)
as controls. In kinase assays, the compound 1f showed
excellent dual inhibition activity toward EGFRWT (IC50 = 1.4 nM) and HER2 (IC50 = 2.1 nM). In
vivo pharmacology evaluation of 1f showed significant
antitumor activity (TGI = 44.2%) in A549 xenografts mice. The current
work provided a feasible solution to optimize anilinoquinazoline-based
inhibitors.