摘要
本研究中,我们基于共晶技术和药效团、分子对接等虚拟筛选,发现了一系列二氢双苯氧卓类化合物可以作为PARP1抑制剂。并经过结构优化,我们发现了一个具有新颖化学结构和与PARP1蛋白有独特结合作用的化合物OL-1(2-(11-(3-(dimethylamino)propylidene)-6,11-dihydrodibenzo[b,e]oxepin)-2-y1)acetohydrazide)。实验证明OL-1具有很强的活性(对PARP1的酶活抑制IC50=0.079μM),同时也抑制PARP调节的芳基化作用及BRAC/基因突变的MDA-MB-436细胞增殖。并且OL-1能够抑制与癌症转移密切相关的细胞转移,在MDA-MB-436细胞移植瘤模型中表现出显著的抗癌活性,且没有明显的毒性。这些结果显示OL-1有一定潜力应用于将来三阴性乳腺癌的治疗中。
In this study,based on co-crystallization studies and pharmacophore-docking-based virtual screening,we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as poly(ADP-ribose) polymerase 1(PARPl) inhibitors.Lead optimization result in the identification of compound OL-1(2-(11-(3-(dimethylamino)propylidene)-6,11- dihydrodibenzo[b,e]oxepin)-2-yl)acetohydrazide),which has a novel chemical scaffold and unique binding interaction with PARPl protein.OL-1 demonstrated excellent potency(inhibiting PARPl enzyme activity with IC50 = 0.079 μM),as well as inhibiting PARP-modulated PARylation and cell proliferation in MDA-MB-436 cells(BRACl mutation).In addition,OL-1 also inhibited cell migration that closely related to cancer metastasis and displayed remarkable anti-tumor efficacy in MDA-MB-436 xenograft model without apparent toxicities.These findings highlight a new small-molecule PAPR1 inhibitor(OL-1) that has the potential to impact future TNBC therapy.
引文
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