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<p>Natural products represent a cornerstone in anticancer drug discovery owing to their structural diversity and unique bioactivities. Among them, matrine—a principal alkaloid derived from the traditional Chinese medicine <i>Sophora flavescens</i>—has attracted attention due to its documented antitumor properties; however, its clinical translation has been severely hampered by inherently low potency. To address this limitation, we designed and synthesized 28 novel matrine-thiophene hybrids via a structure-based molecular hybridization approach. Notably, the lead compound <b>B10</b> exhibited a dramatic enhancement in anticancer efficacy, demonstrating IC₅₀ values of 4.13–5.79 µM against hepatocellular carcinoma (HCC) cell lines, which reflects an improvement of more than 1000-fold compared to the parent matrine, while showing minimal toxicity toward normal hepatocytes. Furthermore, in an in vivo xenograft model, <b>B10</b> (40&#xa0;mg/kg) achieved a tumor growth inhibition rate of 64.2%, outperforming the standard drug sorafenib. Critically, to decipher the underlying mechanism, we employed a proteolysis-targeting chimera (PROTAC) strategy, converting <b>B10</b> into a targeted degrader, <b>K2</b>. This chemical probe enabled us to identify fibroblast growth factor receptor 3 (FGFR3) as a direct target of <b>B10</b> and to elucidate its role in suppressing the FGFR3/PI3K/AKT signaling pathway. Collectively, this study not only presents <b>B10</b> as a highly promising candidate for HCC treatment derived from a natural product scaffold, but also identifies FGFR3 as a novel therapeutic target in HCC, thereby providing an innovative and generalizable platform for target deconvolution and mechanistic investigation of natural product-based agents.</p>

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A novel matrine derivative B10 exerts its anti-liver cancer activity in vitro and in vivo via targeting FGFR3/PI3K/AKT signaling pathway

  • 期刊论文

  • 发表日期：

    2026年1月14日

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  • Xingdong Wang,
  • Yuxin Xie,
  • Zhouxing Hu,
  • Siyi Wang,
  • Manqi Li,
  • Lichuan Wu,
  • Jun Jiang,
  • Lisheng Wang

摘要

Natural products represent a cornerstone in anticancer drug discovery owing to their structural diversity and unique bioactivities. Among them, matrine—a principal alkaloid derived from the traditional Chinese medicine Sophora flavescens—has attracted attention due to its documented antitumor properties; however, its clinical translation has been severely hampered by inherently low potency. To address this limitation, we designed and synthesized 28 novel matrine-thiophene hybrids via a structure-based molecular hybridization approach. Notably, the lead compound B10 exhibited a dramatic enhancement in anticancer efficacy, demonstrating IC₅₀ values of 4.13–5.79 µM against hepatocellular carcinoma (HCC) cell lines, which reflects an improvement of more than 1000-fold compared to the parent matrine, while showing minimal toxicity toward normal hepatocytes. Furthermore, in an in vivo xenograft model, B10 (40 mg/kg) achieved a tumor growth inhibition rate of 64.2%, outperforming the standard drug sorafenib. Critically, to decipher the underlying mechanism, we employed a proteolysis-targeting chimera (PROTAC) strategy, converting B10 into a targeted degrader, K2. This chemical probe enabled us to identify fibroblast growth factor receptor 3 (FGFR3) as a direct target of B10 and to elucidate its role in suppressing the FGFR3/PI3K/AKT signaling pathway. Collectively, this study not only presents B10 as a highly promising candidate for HCC treatment derived from a natural product scaffold, but also identifies FGFR3 as a novel therapeutic target in HCC, thereby providing an innovative and generalizable platform for target deconvolution and mechanistic investigation of natural product-based agents.