Department of Pharmacy, Anorectal Hospital of Chengde Medical University, Chengde 067000, PR China.
Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Hebei Key Laboratory of Nerve Injury and Repair, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, PR China.
Bioorg Chem. 2024 Jul;148:107480. doi: 10.1016/j.bioorg.2024.107480. Epub 2024 May 19.
A novel series of erythrina derivatives as PARP-1/FTase inhibitors were synthesized, and evaluated for their biological activities. Compound T9 had excellent inhibitory effects on cell viability (A549: IC = 1.74 μM; A549/5-Fu: IC = 1.03 μM) and in vitro enzyme activities (PARP-1: IC = 0.40 μM; FTase: IC = 0.067 μM). Molecular docking and point mutation assays demonstrated the interaction of compound T9 with key amino acid residues. The compound T9 exhibited potent anti-proliferation and anti-migration capabilities against A549 and A549/5-Fu cells. PCR array and western blot results showed that compound T9 could effectively inhibit EMT-related proteins in A549 and A549/5-Fu cells, thereby inhibiting the development of lung cancer. Importantly, compound T9 could significantly inhibit tumor growth in the A549 xenograft tumor model (TGI = 65.3 %). In conclusion, this study was the first presentation of the concept of dual-target inhibitors of the PARP-1/FTase enzymes. It also provides the basis for further research and development of novel PARP-1/FTase inhibitors.
一系列新型的桐花树衍生物作为 PARP-1/FTase 抑制剂被合成，并对其生物活性进行了评估。化合物 T9 对细胞活力（A549：IC = 1.74 μM；A549/5-Fu：IC = 1.03 μM）和体外酶活性（PARP-1：IC = 0.40 μM；FTase：IC = 0.067 μM）具有优异的抑制作用。分子对接和点突变试验表明，化合物 T9 与关键氨基酸残基相互作用。化合物 T9 对 A549 和 A549/5-Fu 细胞表现出强大的抗增殖和抗迁移能力。PCR 阵列和 Western blot 结果表明，化合物 T9 能够有效抑制 A549 和 A549/5-Fu 细胞中 EMT 相关蛋白的表达，从而抑制肺癌的发展。重要的是，化合物 T9 能够显著抑制 A549 异种移植肿瘤模型中的肿瘤生长（TGI = 65.3%）。总之，本研究首次提出了 PARP-1/FTase 酶双重靶标抑制剂的概念。它也为进一步研究和开发新型 PARP-1/FTase 抑制剂提供了依据。
