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

Abstract

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.

• Authors: Yilan Ju, Jintao Wu, Xi Yuan, Luqing Zhao, Ganlin Zhang, Chao Li, Renzhong Qiao
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 24 Pg. 11372-11383 (12 27 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 30508379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Antineoplastic Agents
• Polyamines
• Protein Kinase Inhibitors
• Quinazolines
• anilinoquinazoline
• Lapatinib
• Adenosine Triphosphate
• EGFR protein, human
• ErbB Receptors

Topics

• A549 Cells
• Adenosine Triphosphate (metabolism)
• Aniline Compounds (chemistry)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Female
• Humans
• Lapatinib (chemistry, pharmacology)
• Mice, Inbred BALB C
• Molecular Docking Simulation
• Polyamines (chemistry)
• Protein Domains
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Quinazolines (chemistry)
• Xenograft Model Antitumor Assays