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

• Published in: Journal of medicinal chemistry 2020-12, Vol.63 (24), p.15906-15945
• Main 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
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Apoptosis; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Proliferation; Drug Design; Female; Gene Expression Regulation, Neoplastic; Humans; In Vitro Techniques; Lapatinib - chemistry; Mice; Mice, Nude; Molecular Targeted Therapy; Quinazolines - chemical synthesis; Quinazolines - pharmacology; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01647

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 μM) 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 (T 1/2 > 145 min and CLint(mic) < 9.6 mL/min/kg).