Polypharmacology‐Driven Discovery of ZAK‐I‐57: A Potent Multi‐Targeted Benzoxazinone Small Molecule for Hepatocellular Carcinoma Therapy

Hepatocellular carcinoma (HCC) is a deadly disease characterized by a high mortality rate and resistance to conventional therapies, highlighting the need for novel therapeutic interventions. Given the multifaceted nature of HCC pathogenesis, a multitargeted and polypharmacological approach is crucial for effective treatment. This study reports the potent multitargeted and polypharmacological properties of ZAK-I-57, a benzoxazinone derivative, as a potential therapeutic option for HCC. In cell-based model, ZAK-I-57 demonstrated significant in vitro inhibition of proliferation in HCC cells. Utilizing PLC/PRF/5 tumor-bearing and HCC patient-derived tumor xenograft (PDTX) mouse models, we compared the efficacy of ZAK-I-57 with that of sorafenib, the current standard treatment. ZAK-I-57 demonstrated superior tumor suppressive effects at doses of 15 and 30 mg/kg, outperforming sorafenib. Western blot analysis revealed that ZAK-I-57 downregulated the oncogenic proteins EGFR and c-Myc, while promoting apoptosis by increasing Bax and decreasing Bcl-2 expression. Strikingly, ZAK-I-57 exhibited excellent ADMET properties, including high gastrointestinal absorption and good lipophilicity, along with an excellent safety profile, with no significant off-target toxicity in vital organs. In summary, our findings highlight ZAK-I-57 as a new and promising multitarget therapeutic agent for HCC, warranting further clinical investigation to improve patient outcomes.