Pt(II) Complex with FGFR4 Specificity as a Targeted Drug Conjugate for the Treatment of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a highly refractory malignancy, for which treatment relies on molecule targeted therapy and/or conventional chemotherapy in clinic. However, these approaches generally suffer from limited efficacy or severe toxicity, restricting their applications. Guided by the targeted drug conjugate (TDC) strategy, the pharmacophore of lenvatinib was modified by incorporating DN604 (C 6 H 10 N 2 O 5 Pt), a carboplatin analogue, to generate a Pt(II) complex Len-604 (C 30 H 33 ClN 8 O 9 Pt). This compound was found to possess the specific capability to bind to fibroblast growth factor receptor 4 (FGFR4) protein both in vitro and in vivo, facilitating targeted delivery of DN604 to tumor sites and consequently triggering serious DNA damage in cancer cells. It exhibited potent cytotoxicity against human hepatocellular carcinoma cell lines HUH-7 and SMMC-7721, with IC 50 values of 5.62 and 5.64 μM, respectively. Significantly, in HUH-7 xenograft models, Len-604 exhibited stronger antitumor activity than lenvatinib, while showing lower toxicity than cisplatin and its physical mixture with lenvatinib.