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

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.