目前的工作开发了多样的新型 napabucasin-褪黑激素混合物作为强效STAT3抑制剂。几项生物研究表明，许多化合物表现出对不同肿瘤细胞的强效抑制作用。其中，7e化合物对HepG2、MDA-MB-231和A549细胞的抑制作用比 napabucasin 更强，分别具有1.06、1.38和1.3 µM的IC50值。基于荧光偏振分析，7e化合物与STAT3的SH2结构域结合，IC50值为12.95 µM。分子对接进一步证实了7e在STAT3的SH2结构域内的结合方式。进一步的机械学研究表明，7e抑制STAT3(Y705)的活化，从而降低STAT3的下游基因（CyclinD1、Bcl-2和c-Myc）的表达，而不是影响p-STAT1的表达。同时，其上游激酶JAK2和旁路激酶Erk1/2的磷酸化水平保持不变。同时，7e以浓度依赖的方式诱导癌细胞凋亡。值得注意的是，20mg/kg (i.p.)的7e化合物可在体内抑制小鼠HepG2异种移植的发展，且不会出现体重下降，表明它可能是一种有效的抗肿瘤剂。版权所有©2023 Elsevier Inc.。保留所有权利。

The current work developed diverse novel napabucasin-melatonin hybrids as potent STAT3 inhibitors. Several biological studies have suggested many compounds demonstrating potent inhibition against different tumor cells. Among these, compound 7e depicted enhanced inhibition against HepG2, MDA-MB-231, and A549 cells than napabucasin, with IC50 values of 1.06, 1.38, and 1.3 µM, respectively. Based on fluorescence polarization analysis, compound 7e was bound to the SH2 domain in STAT3, with an IC50 value of 12.95 µM. Molecular docking further confirmed the 7e binding mode inside the SH2 domain of STAT3. Further mechanistic studies indicated that 7e inhibited the activation of STAT3 (Y705), and thus reduced the expression of STAT3 downstream genes (CyclinD1, Bcl-2 and c-Myc) instead of affecting p-STAT1 expression. Meanwhile, the phosphorylation levels of its upstream kinases JAK2 and bypass kinase Erk1/2 remain unaffected. Simultaneously, 7e induced cancer cell apoptosis in a concentration-dependent manner. Significantly, 20 mg/kg (i.p.) compound 7e suppressed the mouse HepG2 xenograft development in vivo without body weight loss, suggesting that it could be an effective antitumor agent.Copyright © 2023 Elsevier Inc. All rights reserved.