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Natural Product-Inspired Discovery of Naphthoquinone-Furo-Piperidine Derivatives as Novel STAT3 Inhibitors for the Treatment of Triple-Negative Breast Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-03 , DOI: 10.1021/acs.jmedchem.4c00872 Chengcheng Fan 1 , Shengying Lou 1 , Chenjun Shen 2 , Jialing Liao 1 , Hao Ni 1 , Siyu Chen 1 , Zhihui Zhu 2 , Xueping Hu 3 , Wei Xie 1 , Huajun Zhao 2 , Sunliang Cui 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-03 , DOI: 10.1021/acs.jmedchem.4c00872 Chengcheng Fan 1 , Shengying Lou 1 , Chenjun Shen 2 , Jialing Liao 1 , Hao Ni 1 , Siyu Chen 1 , Zhihui Zhu 2 , Xueping Hu 3 , Wei Xie 1 , Huajun Zhao 2 , Sunliang Cui 1
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Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and STAT3 has emerged as an effective drug target for TNBC treatment. Herein, we employed a scaffold-hopping strategy of natural products to develop a series of naphthoquinone-furopiperidine derivatives as novel STAT3 inhibitors. The in vitro assay showed that compound 10g possessed higher antiproliferative activity than Cryptotanshinone and Napabucasin against TNBC cell lines, along with lower toxicity and potent antitumor activity in a TNBC xenograft model. Mechanistically, 10g could inhibit the phosphorylation of STAT3 and the binding affinity was determined by the SPR assay (KD = 8.30 μM). Molecule docking studies suggested a plausible binding mode between 10g and the SH2 domain, in which the piperidine fragment and the terminal hydroxy group of 10g played an important role in demonstrating the success of this evolution strategy. These findings provide a natural product-inspired novel STAT3 inhibitor for TNBC treatment.
中文翻译：
受天然产物启发发现萘醌-呋喃-哌啶衍生物作为新型 STAT3 抑制剂用于治疗三阴性乳腺癌
三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型，STAT3 已成为 TNBC 治疗的有效药物靶点。在此，我们采用天然产物的支架跳跃策略开发了一系列萘醌-呋喃哌啶衍生物作为新型STAT3抑制剂。体外试验表明，化合物10g对 TNBC 细胞系具有比 Cryptotanshinone 和 Napabucasin 更高的抗增殖活性，并且在 TNBC 异种移植模型中具有较低的毒性和有效的抗肿瘤活性。从机制上讲， 10g可以抑制 STAT3 的磷酸化，并通过 SPR 测定确定结合亲和力（ K D = 8.30 μM）。分子对接研究表明10g与SH2结构域之间存在一种合理的结合模式，其中哌啶片段和10g的末端羟基在证明这种进化策略的成功方面发挥了重要作用。这些发现为 TNBC 治疗提供了一种受天然产物启发的新型 STAT3 抑制剂。
更新日期：2024-09-03
中文翻译：
受天然产物启发发现萘醌-呋喃-哌啶衍生物作为新型 STAT3 抑制剂用于治疗三阴性乳腺癌
三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型，STAT3 已成为 TNBC 治疗的有效药物靶点。在此，我们采用天然产物的支架跳跃策略开发了一系列萘醌-呋喃哌啶衍生物作为新型STAT3抑制剂。体外试验表明，化合物10g对 TNBC 细胞系具有比 Cryptotanshinone 和 Napabucasin 更高的抗增殖活性，并且在 TNBC 异种移植模型中具有较低的毒性和有效的抗肿瘤活性。从机制上讲， 10g可以抑制 STAT3 的磷酸化，并通过 SPR 测定确定结合亲和力（ K D = 8.30 μM）。分子对接研究表明10g与SH2结构域之间存在一种合理的结合模式，其中哌啶片段和10g的末端羟基在证明这种进化策略的成功方面发挥了重要作用。这些发现为 TNBC 治疗提供了一种受天然产物启发的新型 STAT3 抑制剂。
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