2. Academic Validation
  3. Design and synthesis of Lapatinib derivatives containing a branched side chain as HER1/HER2 targeting antitumor drug candidates

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.
Aifeng Lyu 1,  Lei Fang 2,  Shaohua Gou 3
Affiliations

Affiliations

  • 1 Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Hansoh Pharmceutical Corporation, Lianyungang 222000, China.
  • 2 Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
  • 3 Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.
PMID: 25305330 DOI: 10.1016/j.ejmech.2014.10.006
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.

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