HER2 Kinase-Targeted Breast Cancer Therapy: Design, Synthesis, and In Vitro and In Vivo Evaluation of Novel Lapatinib Congeners as Selective and Potent HER2 Inhibitors with Favorable Metabolic Stability. Academic Article uri icon


  • HER2 kinase as a well-established target for breast cancer (BC) therapy is associated with aggressive clinical outcomes; thus, herein we present structural optimization for HER2-selective targeting. HER2 profiling of the developed derivatives demonstrated potent and selective inhibitions (IC50: 5.4-12 nM) compared to lapatinib (IC50: 95.5 nM). Favorably, 17d exhibited minimum off-target kinase activation. NCI-5-dose screening revealed broad-spectrum activities (GI50: 1.43-2.09 M) and 17d had a remarkable selectivity toward BC. Our compounds revealed significant selective and potent antiproliferative activities (20-fold) against HER2+ (AU565, BT474) compared to HER2(-) cells. At 0.1 IC50, 15i, 17d, and 25b inhibited pERK1/2 and pAkt by immunoblotting. Furthermore, 17d demonstrated potent in vivo tumor regression against the BT474 xenograft model. Notably, a metastasis case was observed in the vehicle but not in the test mice groups. CD-1 mice metabolic stability assay revealed high stability and low intrinsic clearance of 17d (T1/2 > 145 min and CLint(mic) < 9.6 mL/min/kg).

published proceedings

  • J Med Chem

author list (cited authors)

  • Elwaie, T. A., Abbas, S. E., Aly, E. I., George, R. F., Ali, H., Kraiouchkine, N., ... Ali, H. I.

citation count

  • 5

complete list of authors

  • Elwaie, Tamer A||Abbas, Safinaz E||Aly, Enayat I||George, Riham F||Ali, Hamdy||Kraiouchkine, Nikolai||Abdelwahed, Khaldoun S||Fandy, Tamer E||El Sayed, Khalid A||Abd Elmageed, Zakaria Y||Ali, Hamed I

publication date

  • December 2020