Design and synthesis of Lapatinib derivatives containing a branched side chain as HER1/HER2 targeting antitumor drug candidates

Eur J Med Chem. 2014 Nov 24:87:631-42. doi: 10.1016/j.ejmech.2014.10.006. Epub 2014 Oct 5.

Abstract

A series of Lapatinib derivatives were designed and prepared by changing the straight alkyl side chain of Lapatinib into a branched one. ELISA assay and western blot analysis showed that these derivatives can significantly inhibit HER1/HER2 as well as their downstream signal transduction proteins. In vitro cytotoxicity assay revealed that these compounds had potent cytotoxic effect against the HER1/HER2-overexpressing cancer cells. A representive compound, 2i, showed potent in vivo antitumor activity comparable to Lapatinib, which was found to block the cell-cycle progression of BT474 cells in the G1 phase causing tumor cell apoptosis in the flow cytometry study. Moreover, the pharmacokinetic investigation on 2i also indicated it had a good performance on both absorption and elimination profiles.

Keywords: Antitumor; HER1/HER2 targeting; Lapatinib derivatives; Tyrosine kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Blotting, Western
  • Cell Line, Tumor
  • ErbB Receptors / drug effects*
  • Flow Cytometry
  • Humans
  • In Vitro Techniques
  • Lapatinib
  • Molecular Docking Simulation
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology
  • Receptor, ErbB-2 / drug effects*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Quinazolines
  • Lapatinib
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2