HER2 Kinase-Targeted Breast Cancer Therapy: Design, Synthesis, and <i>In Vitro</i> and <i>In Vivo</i> Evaluation of Novel Lapatinib Congeners as Selective and Potent HER2 Inhibitors with Favorable Metabolic Stability

Abstract

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, <b>17d</b> exhibited minimum off-target kinase activation. NCI-5-dose screening revealed broad-spectrum activities (GI₅₀: 1.43-2.09 μM) and <b>17d</b> 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, <b>15i</b>, <b>17d</b>, and <b>25b</b> inhibited pERK1/2 and pAkt by immunoblotting. Furthermore, <b>17d</b> demonstrated potent <i>in vivo</i> 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 <b>17d</b> (<i>T</i>_1/2 > 145 min and CL_int(mic) < 9.6 mL/min/kg).