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 (C6H10N2O5Pt), a carboplatin analogue, to
generate a Pt(II) complex Len-604 (C30H33ClN8O9Pt). 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 IC50 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.