2. Academic Validation
  3. Gefitinib-Tamoxifen Hybrid Ligands as Potent Agents against Triple-Negative Breast Cancer

Gefitinib-Tamoxifen Hybrid Ligands as Potent Agents against Triple-Negative Breast Cancer

  • J Med Chem. 2022 Mar 24;65(6):4616-4632. doi: 10.1021/acs.jmedchem.1c01646.
Carine M Abdelmalek 1 2,  Zexi Hu 3 4,  Thales Kronenberger 2 3 4,  Jenni Küblbeck 5 6,  Franziska J M Kinnen 2,  Salma S Hesse 1,  Afsin Malik 7,  Mark Kudolo 2,  Raimund Niess 2,  Matthias Gehringer 2 4,  Lars Zender 3 4,  Paula A Witt-Enderby 7,  Darius P Zlotos 1,  Stefan A Laufer 2 4 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, 11835 New Cairo City, Cairo, Egypt.
  • 2 Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
  • 3 Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital of Tübingen, 72076 Tübingen, Germany.
  • 4 Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', University of Tübingen, 72076 Tübingen, Germany.
  • 5 A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland.
  • 6 School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland.
  • 7 School of Pharmacy, Division of Pharmaceutical, Administrative and Social Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States.
  • 8 Tübingen Center for Academic Drug Discovery, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
PMID: 35286086 DOI: 10.1021/acs.jmedchem.1c01646
Abstract

Anticancer drug conjugates may benefit from simultaneous action at two targets potentially overcoming the drawbacks of current Cancer treatment, such as insufficient efficacy, high toxicity, and development of resistance. Compared to a combination of two single-target drugs, they may offer an advantage of pharmacokinetic simplicity and fewer drug-drug interactions. Here, we report a series of compounds connecting tamoxifen or endoxifen with the EGFR-inhibitor gefitinib via a covalent linkage. These hybrid ligands retain both ER antagonist activity and EGFR inhibition. The most potent analogues exhibited single-digit nanomolar activities at both targets. The amide-linked endoxifen-gefitinib drug conjugates 17b and 17c demonstrated the most favorable anti-cancer profile in cellular viability assays on MCF7, MDA-MB-231, MDA-MB-468, and BT-549 breast Cancer cells. Most importantly, in TNBC cells 17b and 17c displayed nanomolar IC50-values (380 nM - 970 nM) and were superior in their anti-cancer activity compared to their control compounds and combinations thereof.

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