Discovery of Oral Natural Benzofuranoid <i>p</i>‑Terphenyl Derivative CHNQD-03301 as a Potent Hypoxia-Inducible Factor-1α Signaling Inhibitor for Cancer Therapy

Hypoxia in the tumor microenvironment drives aggressive cancer phenotypes, and hypoxia-inducible factor-1α (HIF-1α) is a potential therapeutic target for anticancer drugs. We screened for HIF-1α inhibitors from the compound library. With terphenyllin derivative 10 as a hit, a small molecular library of 27 benzofuranoid p-terphenyls was constructed. Among them, CHNQD-03301 (20) with a rare acetonide group exhibited the strongest HIF-1α inhibitory activity (IC50 = 10.97 nM). Mechanically, it promoted the proteasomal degradation of HIF-1α protein, leading to its significant suppression. Further studies demonstrated its ability to reverse HIF accumulation-induced angiogenesis and mitigate the HIF-induced erythrocytosis phenotype in zebrafish models. Importantly, CHNQD-03301 significantly suppressed tumor growth (TGI = 51.0% and 52.0%) at 1 mg/kg (p.o.) in HCT116 xenograft and MB49 allograft models, respectively. Meanwhile, CHNQD-03301 demonstrated favorable pharmacokinetic properties and a safety profile. In conclusion, this study provided promising oral HIF-1α signaling inhibitor CHNQD-03301 for further development in cancer therapy.