Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Eur J Med Chem. 2021 Jun 5;218:113362. doi: 10.1016/j.ejmech.2021.113362. Epub 2021 Mar 17.
Signal transducer and activator of transcription 3 (STAT3) has been confirmed as an attractive therapeutic target for cancer therapy. Herein, we designed and synthesized a series of N-substituted Sulfamoylbenzamide STAT3 inhibitors based on small-molecule STAT3 inhibitor Niclosamide. Compound B12, the best active compound of this series, was identified as an inhibitor of IL-6/STAT3 signaling with an IC of 0.61-1.11 μM in MDA-MB-231, HCT-116 and SW480 tumor cell lines with STAT3 overexpression, by inhibiting the phosphorylation of STAT3 of Tyr705 residue and the expression of STAT3 downstream genes, inducing apoptosis and inhibiting the migration of cancer cells. Furthermore, in vivo study revealed that compound B12 suppressed the MDA-MB-231 xenograft tumor growth in nude mice at the dose of 30 mg/kg (i.g.), which has better antitumor activity than the positive control Niclosamide. More importantly, B12 is an orally bioavailable anticancer agent as a promising candidate for further development.
信号转导子和转录激活子 3（STAT3）已被证实是癌症治疗的一个有吸引力的治疗靶点。在此，我们设计并合成了一系列基于小分子 STAT3 抑制剂尼立达唑的 N-取代磺酰胺苯甲酰胺 STAT3 抑制剂。该系列中最好的活性化合物 B12 被鉴定为 IL-6/STAT3 信号通路的抑制剂，在 MDA-MB-231、HCT-116 和 SW480 肿瘤细胞系中，对 STAT3 过表达的细胞，IC50 为 0.61-1.11 μM，通过抑制 STAT3 的 Tyr705 残基磷酸化和 STAT3 下游基因的表达，诱导细胞凋亡和抑制癌细胞迁移。此外，体内研究表明，化合物 B12 在 30mg/kg（ig）剂量下抑制裸鼠 MDA-MB-231 异种移植肿瘤生长，其抗肿瘤活性优于阳性对照尼立达唑。更重要的是，B12 是一种口服生物利用的抗癌药物，是进一步开发的有前途的候选药物。
