Abdelmalek Carine M, Hu Zexi, Kronenberger Thales, Küblbeck Jenni, Kinnen Franziska J M, Hesse Salma S, Malik Afsin, Kudolo Mark, Niess Raimund, Gehringer Matthias, Zender Lars, Witt-Enderby Paula A, Zlotos Darius P, Laufer Stefan A
Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, 11835 New Cairo City, Cairo, Egypt.
Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
J Med Chem. 2022 Mar 24;65(6):4616-4632. doi: 10.1021/acs.jmedchem.1c01646. Epub 2022 Mar 14.
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 and 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 and displayed nanomolar IC-values (380 nM - 970 nM) and were superior in their anti-cancer activity compared to their control compounds and combinations thereof.
抗癌药物偶联物可能受益于对两个靶点的同时作用，这有可能克服当前癌症治疗的缺点，如疗效不足、高毒性和耐药性的产生。与两种单靶点药物的联合使用相比，它们可能具有药代动力学简单和药物相互作用较少的优势。在此，我们报告了一系列通过共价键将他莫昔芬或4-羟基他莫昔芬与表皮生长因子受体（EGFR）抑制剂吉非替尼连接起来的化合物。这些杂合配体保留了雌激素受体（ER）拮抗剂活性和EGFR抑制作用。最有效的类似物在两个靶点上均表现出个位数的纳摩尔活性。酰胺连接的4-羟基他莫昔芬-吉非替尼药物偶联物在MCF7、MDA-MB-231、MDA-MB-468和BT-549乳腺癌细胞的细胞活力测定中显示出最有利的抗癌谱。最重要的是，在三阴性乳腺癌（TNBC）细胞中，[具体化合物]显示出纳摩尔的半数抑制浓度（IC）值（380 nM - 970 nM），并且与其对照化合物及其组合相比，其抗癌活性更优。
