Table2_Pharmacokinetics, tissue distribution, and antitumor activity of a novel compound, NY-2, in non-small cell lung cancer.doc

Introduction: 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 in vivo.
Method: 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) in vitro and in vivo.
Results: 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.
Conclusion: 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.

引言：ZLDI-8是一种具有较强抗肿瘤活性的解整合素-金属蛋白酶17（ADAM-17）抑制剂，可作用于Notch信号通路（Notch signaling pathway）。为进一步优化其结构、提升活性，研究人员合成了一系列ZLDI-8衍生物。经体外初步活性筛选，NY-2为其中活性最优的衍生物，且体内给药后未观察到明显毒性。
方法：本研究旨在考察化合物NY-2的药代动力学特征、组织分布情况、肝毒性与肾毒性，以及其在体内外对非小细胞肺癌（non-small cell lung cancer, NSCLC）的抗肿瘤活性。
结果：NY-2的体内药代动力学参数优于母药ZLDI-8。组织分布分析显示，大鼠尾静脉注射6 mg/kg的NY-2后，其在肺部的药物浓度最高，据此研究团队推测NY-2或可用于非小细胞肺癌的治疗。体外实验结果表明，NY-2可呈浓度依赖性地显著抑制非小细胞肺癌细胞的肿瘤集落形成、侵袭与迁移能力，同时上调乳酸脱氢酶（lactate dehydrogenase, LDH）活性并诱导细胞凋亡。此外，NY-2可抑制裸鼠体内的肺转移灶形成，且对裸鼠主要脏器无明显毒性。
结论：与母药ZLDI-8相比，NY-2的抗肿瘤活性与安全性均更优。NY-2可通过靶向ADAM-17，同时调控下游Notch1与整合素β1（integrinβ1）信号通路以发挥抗肿瘤作用。综上，NY-2有望成为一款潜在的抗肿瘤候选药物，可有效抑制非小细胞肺癌的发生与发展。