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

• Published in: MedComm
• Main Authors: Shakeel Ahmad Khan, Huihai Yang, Fan Ying, Chin Ngok Chu, Terence Kin Wah Lee
• Format: Article
• Language: English
• Published: Wiley 2025-08-01
• Subjects: benzoxazinone derivatives; hepatocellular carcinoma; multi‐targeted therapy; polypharmacology; tumor suppression
• Online Access: https://doi.org/10.1002/mco2.70291

ABSTRACT 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.