Amenta Arianna, Comi Susanna, Kravicz Marcelo, Sesana Silvia, Antoniou Antonia, Passarella Daniele, Seneci Pierfausto, Pellegrino Sara, Re Francesca
Department of Chemistry, University of Milan Milan Italy.
School of Medicine and Surgery, University of Milano-Bicocca Monza Italy
RSC Med Chem. 2024 Oct 3;16(1):168-78. doi: 10.1039/d4md00517a.
Pimasertib, a potent antiproliferative drug, has been extensively studied for treating cancers characterized by dysregulation in the ERK/MAPK signaling pathway, such as melanoma. However, its therapeutic efficacy would greatly benefit from an increased selectivity for tumour cells and a longer half-life. Such improvements may be achieved by combining the rational design of a prodrug with its encapsulation in a potential nanodelivery system. For this reason, we synthesized a glutathione (GSH)-responsive putative prodrug of pimasertib (PROPIMA), which contains a redox-sensitive disulphide linker that can be processed by GSH to activate pimasertib. The synthesis of PROPIMA and its biological activity on a human melanoma cell line as a model are described. The results showed that PROPIMA, either free or embedded in liposomes, selectively inhibits cell proliferation and cell viability, reducing by about 5-fold the levels of pERK. Additionally, PROPIMA shows stronger inhibition of the cancer cell migration than the parent drug.
匹马西替布是一种强效抗增殖药物，已针对治疗以ERK/MAPK信号通路失调为特征的癌症（如黑色素瘤）进行了广泛研究。然而，其治疗效果若能提高对肿瘤细胞的选择性并延长半衰期，将大有裨益。通过将前药的合理设计与封装在潜在的纳米递送系统中相结合，或许可以实现这些改进。因此，我们合成了一种匹马西替布的谷胱甘肽（GSH）响应性推定前药（PROPIMA），它含有一个氧化还原敏感的二硫键连接子，可被GSH作用以激活匹马西替布。本文描述了PROPIMA的合成及其对人黑色素瘤细胞系作为模型的生物学活性。结果表明，游离或包埋于脂质体中的PROPIMA均能选择性抑制细胞增殖和细胞活力，使pERK水平降低约5倍。此外，PROPIMA对癌细胞迁移的抑制作用比母体药物更强。
