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-1<i>α</i> (HIF-1<i>α</i>) is a potential therapeutic target for anticancer drugs. We screened for HIF-1<i>α</i> inhibitors from the compound library. With terphenyllin derivative <b>10</b> as a hit, a small molecular library of 27 benzofuranoid <i>p</i>-terphenyls was constructed. Among them, CHNQD-03301 (<b>20)</b> with a rare acetonide group exhibited the strongest HIF-1<i>α</i> inhibitory activity (IC₅₀ = 10.97 nM). Mechanically, it promoted the proteasomal degradation of HIF-1<i>α</i> 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-1<i>α</i> signaling inhibitor CHNQD-03301 for further development in cancer therapy.