Elwaie, T. A., S. E. Abbas, E. I. Aly, R. F. George, H. Ali, N. Kraiouchkine, K. S. Abdelwahed, T. E. Fandy, K. A. El Sayed, Z. Y. Abd Elmageed, et al.,
"HER2 Kinase-Targeted Breast Cancer Therapy: Design, Synthesis, and and Evaluation of Novel Lapatinib Congeners as Selective and Potent HER2 Inhibitors with Favorable Metabolic Stability.",
Journal of medicinal chemistry, vol. 63, issue 24, pp. 15906-15945, 2020.
AbstractHER2 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 (IC: 5.4-12 nM) compared to lapatinib (IC: 95.5 nM). Favorably, exhibited minimum off-target kinase activation. NCI-5-dose screening revealed broad-spectrum activities (GI: 1.43-2.09 μM) and 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 IC, , , and inhibited pERK1/2 and pAkt by immunoblotting. Furthermore, demonstrated potent 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 ( > 145 min and CL < 9.6 mL/min/kg).
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