2. Academic Validation
  3. 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

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

  • J Med Chem. 2020 Dec 24;63(24):15906-15945. doi: 10.1021/acs.jmedchem.0c01647.
Tamer A Elwaie 1 2,  Safinaz E Abbas 2,  Enayat I Aly 2,  Riham F George 2,  Hamdy Ali 1,  Nikolai Kraiouchkine 3,  Khaldoun S Abdelwahed 4,  Tamer E Fandy 5,  Khalid A El Sayed 4,  Zakaria Y Abd Elmageed 1 6,  Hamed I Ali 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, Kingsville, Texas 78363, United States.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
  • 3 Department of Physical and Environmental Sciences, Texas A&M University, Corpus Christi, Texas 78412, United States.
  • 4 School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, Louisiana 71201, United States.
  • 5 Department of Pharmaceutical & Administrative Sciences, School of Pharmacy, University of Charleston, Charleston, West Virginia 25304, United States.
  • 6 Department of Pharmacology, Edward Via College of Osteopathic Medicine, University of Louisiana at Monroe, Monroe, Louisiana 71203, United States.
PMID: 33314925 DOI: 10.1021/acs.jmedchem.0c01647
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, 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 (T1/2 > 145 min and CLint(mic) < 9.6 mL/min/kg).

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