Zhang Yingshi, Xu Chang, Xu Xiangbo, Ma Lingxiang, Li Ruolan, Xu Zihua, Zhao Qingchun
Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, Liaoning, China.
Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
Front Pharmacol. 2023 Jan 16;13:1074576. doi: 10.3389/fphar.2022.1074576. eCollection 2022.
ZLDI-8, which has a relatively strong antitumor activity, is an inhibitor of ADAM-17 and acts on the Notch signaling pathway. To further optimize its structure and improve its activity, a series of derivatives of ZLDI-8 was synthesized. NY-2 was the most effective derivative based on preliminary activity screening in vitro, with no obvious toxicity after administration . The study aimed to determine the pharmacokinetics, tissue distribution, hepatotoxicity, nephrotoxicity, and antitumor activity of compound NY-2 on non-small cell lung cancer (NSCLC) and . The in vivo pharmacokinetics parameters of NY-2 were better than those of ZLDI-8. The tissue distribution analysis showed that tail vein injection of 6 mg/kg of NY-2 in rats resulted in the highest concentration in the lung, so we hypothesized that NY-2 might be effective in the treatment of non-small cell lung cancer. In vitro assays showed that NY-2 significantly inhibited tumor colony formation, invasion, and migration and increased LDH activity and apoptosis in a concentration-dependent manner in non-small cell lung cancer cells. NY-2 also inhibited the formation of lung metastases without significant toxicity to major organs in nude mice. Compared with the parent compound, ZLDI-8, the activity and safety of NY-2 were higher. NY-2 acts on ADAM17 and simultaneously affects the downstream Notch1 and integrinβ1 signaling pathways resulting in antitumor activity. Thus, NY-2 could be a potential antitumor agent, inhibiting the organization and development of non-small cell lung cancer.
ZLDI-8具有较强的抗肿瘤活性，是一种ADAM-17抑制剂，作用于Notch信号通路。为进一步优化其结构并提高活性，合成了一系列ZLDI-8的衍生物。基于体外初步活性筛选，NY-2是最有效的衍生物，给药后无明显毒性。该研究旨在确定化合物NY-2对非小细胞肺癌（NSCLC）的药代动力学、组织分布、肝毒性、肾毒性和抗肿瘤活性。NY-2的体内药代动力学参数优于ZLDI-8。组织分布分析表明，在大鼠尾静脉注射6mg/kg的NY-2后，肺中的浓度最高，因此我们推测NY-2可能对非小细胞肺癌的治疗有效。体外试验表明，NY-2在非小细胞肺癌细胞中以浓度依赖的方式显著抑制肿瘤集落形成、侵袭和迁移，并增加LDH活性和凋亡。NY-2还抑制裸鼠肺转移的形成，对主要器官无明显毒性。与母体化合物ZLDI-8相比，NY-2的活性和安全性更高。NY-2作用于ADAM17，同时影响下游Notch1和整合素β1信号通路，从而产生抗肿瘤活性。因此，NY-2可能是一种潜在的抗肿瘤药物，可抑制非小细胞肺癌的组织和发展。
