Porębska Natalia, Chorążewska Aleksandra, Ciura Krzysztof, Pomorski Adam, Krężel Artur, Opaliński Łukasz
Department of Medical Biotechnology, Faculty of Biotechnology, University of Wroclaw, F. Joliot-Curie 14a, 50-383 Wroclaw, Poland.
Department of Chemical Biology, Faculty of Biotechnology, University of Wroclaw, F. Joliot-Curie 14a, 50-383 Wroclaw, Poland.
J Med Chem. 2025 Jul 10;68(13):13872-13886. doi: 10.1021/acs.jmedchem.5c00782. Epub 2025 Jun 29.
Breast cancer is the most common malignancy in women, with approximately 20-30% of all diagnosed cases characterized by HER2 overexpression. Several HER2-targeted cytotoxic conjugates have been developed, but their efficacy is limited. One of the main obstacles restraining the effectiveness of HER2-specific cytotoxic conjugates is their low internalization, as HER2 is immobile mainly on the cell surface. Therefore, there is a need to develop novel HER2-selective cytotoxic conjugates that will overcome HER2 immovability and, by this, ensure efficient drug delivery into HER2-overexpressing cancer cells. Here, we present a novel system for generating high affinity, self-assembling, inherently fluorescent, and multivalent HER2 ligands. The developed HER2-specific ligands largely overcome the innate stability of HER2 in the plasma membrane by triggering clathrin-independent aggregation-dependent endocytosis of the receptor. To exploit the pro-endocytic potential of developed proteins, we constructed the tetravalent fluorescent cytotoxic conjugate TetraF-vcMMAE and demonstrated its high potency and selectivity against HER2+ breast cancer cells.
乳腺癌是女性中最常见的恶性肿瘤，所有确诊病例中约20%-30%的特征为HER2过表达。已经开发了几种针对HER2的细胞毒性缀合物，但其疗效有限。限制HER2特异性细胞毒性缀合物有效性的主要障碍之一是它们的内化率低，因为HER2主要固定在细胞表面。因此，需要开发新型的HER2选择性细胞毒性缀合物，以克服HER2的固定性，并由此确保将药物有效地递送至HER2过表达的癌细胞中。在此，我们展示了一种用于生成高亲和力、自组装、固有荧光且多价的HER2配体的新型系统。所开发的HER2特异性配体通过触发受体的网格蛋白非依赖性聚集依赖性内吞作用，在很大程度上克服了HER2在质膜中的固有稳定性。为了利用所开发蛋白质的促内吞潜力，我们构建了四价荧光细胞毒性缀合物TetraF-vcMMAE，并证明了其对HER2+乳腺癌细胞的高效力和选择性。
