Identification of Novel Anti-Liver Cancer Small Molecules with Better Therapeutic Index than Sorafenib via Zebrafish...

Area of Science:

• Oncology
• Pharmacology
• Zebrafish Models

Background:

• Hepatocellular carcinoma (HCC) is a major global cause of cancer mortality.
• Sorafenib was the sole FDA-approved drug for advanced HCC, highlighting the need for novel therapeutics.

Purpose of the Study:

• To evaluate the efficacy and safety of two novel tyrosine kinase inhibitors, 419S1 and 420S1, against HCC using a zebrafish screening platform.
• To compare these compounds with Sorafenib in preclinical models.

Main Methods:

• Established a zebrafish drug screening platform for HCC.
• Assessed anti-angiogenesis, toxicity (hepatotoxicity, embryonic toxicity), and therapeutic index (LC50/IC50) of 419S1, 420S1, and Sorafenib in transgenic zebrafish embryos.
• Administered compounds to adult transgenic zebrafish with HCC via retro-orbital injection or oral gavage.
• Utilized patient-derived-xenograft assays to evaluate anti-cancer proliferation effects.

Main Results:

• All three compounds displayed anti-angiogenic properties.
• 419S1 exhibited significantly lower toxicity and a higher therapeutic index compared to 420S1 and Sorafenib.
• Compounds 419S1 and 420S1 demonstrated superior efficacy in reducing HCC proliferation in both zebrafish and patient-derived-xenograft models compared to Sorafenib.
• Treatment reversed pathological features and normalized cell-cycle-related gene expression and proliferation markers in zebrafish models.

Conclusions:

• The zebrafish platform is effective for screening novel HCC therapeutics.
• Compounds 419S1 and 420S1 represent promising, safer alternatives to Sorafenib for advanced HCC treatment.
• Further development of these compounds could lead to more effective and personalized medicine for liver cancer.