Targeting Hepatocellular Carcinoma with TH3424: A Promising AKR1C3-Selective Prodrug

Hepatocellular carcinoma (HCC) is a common and deadly cancer with limited effective treatment options. Overexpression of the enzyme AKR1C3 is associated with resistance to radiation and chemotherapy and is found in the majority of HCC tumors. A new prodrug, TH3424, has been developed that releases a DNA alkylating agent in the presence of activated AKR1C3.

In vitro tests have demonstrated TH3424's potency in eliminating HCC cells with high AKR1C3 expression levels, showing an IC50 of less than 10 nM with a 2-hour exposure. However, it is less effective in cells with low or no AKR1C3 expression. The activity of TH3424 is directly related to AKR1C3 expression levels, as its potency is significantly reduced when combined with an AKR1C3 inhibitor.

Promising in vivo results have been observed in orthotopic and patient-derived disease (PDX) liver cancer models, with effective dosing as low as 1.5mg/kg weekly. TH3424 has shown superior efficacy compared to Sorafenib, the only currently approved drug for late-stage liver cancer. In an orthotopic HepG2 mouse model, a high percentage of mice treated with TH3424 were tumor-free at day 35.

In summary, TH3424 represents a highly selective prodrug for AKR1C3 overexpressing HCC cells, with significant in vitro and in vivo antitumor activity, and may offer a more effective therapeutic option for HCC patients.