Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Chem. 2024 Jun;147:107371. doi: 10.1016/j.bioorg.2024.107371. Epub 2024 Apr 15.
Due to the strong selectivity and permeability of tumor tissue, anti-cancer peptide-drug conjugates (PDCs) can accumulate high concentration of toxic payloads at the target, effectively killing tumor cells. This approach holds great promise for tumor-targeted treatment. In our previous study, we identified the optimal peptide P1 (NPNWGRSWYNQRFK) targeting HER2 from pertuzumab, a monoclonal antibody that blocks the HER2 signaling pathway. Here, a series of PDCs were constructed through connecting P1 and CPT with different linkers. Among these, Z8 emerged as the optimal compound, demonstrating good antitumor activity and targeting ability in biological activity tests. Z8 exhibited IC values of 1.04 ± 0.24 μM and 1.91 ± 0.71 μM against HER2-positive SK-BR-3 and NCI-N87 cells, respectively. Moreover, superior antitumor activity and higher biosafety of Z8 were observed compared to the positive control CPT in vivo, suggesting a novel idea for the construction of PDCs.
由于肿瘤组织具有较强的选择性和通透性，抗癌肽-药物偶联物（PDCs）可以在靶部位积聚高浓度的毒性有效载荷，有效杀死肿瘤细胞。这种方法为肿瘤靶向治疗带来了很大的希望。在我们之前的研究中，我们从曲妥珠单抗（一种阻断 HER2 信号通路的单克隆抗体）中鉴定出针对 HER2 的最佳肽 P1（NPNWGRSWYNQRFK）。在这里，通过连接不同连接子的 P1 和 CPT 构建了一系列 PDC。其中，Z8 表现出最佳的化合物，在生物活性测试中表现出良好的抗肿瘤活性和靶向能力。Z8 对 HER2 阳性 SK-BR-3 和 NCI-N87 细胞的 IC 值分别为 1.04±0.24 μM 和 1.91±0.71 μM。此外，与体内阳性对照 CPT 相比，Z8 表现出更好的抗肿瘤活性和更高的生物安全性，这为 PDC 的构建提供了新的思路。
