PUBLICATION
Discovery of Oral Natural Benzofuranoid p-Terphenyl Derivative CHNQD-03301 as a Potent Hypoxia-Inducible Factor-1α Signaling Inhibitor for Cancer Therapy
- Authors
- Wang, C.F., Cui, X.N., Lv, L.X., Wang, W.H., Jing, Q.Q., Yin, J.N., Cao, X.Z., Wei, M.Y., Lu, L., Shao, C.L.
- ID
- ZDB-PUB-251030-2
- Date
- 2025
- Source
- Journal of medicinal chemistry : (Journal)
- Registered Authors
- Lu, Ling
- Keywords
- none
- MeSH Terms
-
- Administration, Oral
- Animals
- Antineoplastic Agents*/administration & dosage
- Antineoplastic Agents*/chemistry
- Antineoplastic Agents*/pharmacokinetics
- Antineoplastic Agents*/pharmacology
- Antineoplastic Agents*/therapeutic use
- Benzofurans*/administration & dosage
- Benzofurans*/chemistry
- Benzofurans*/pharmacokinetics
- Benzofurans*/pharmacology
- Benzofurans*/therapeutic use
- Cell Line, Tumor
- Drug Discovery*
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit*/antagonists & inhibitors
- Hypoxia-Inducible Factor 1, alpha Subunit*/metabolism
- Mice
- Signal Transduction/drug effects
- Structure-Activity Relationship
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 41159374 Full text @ J. Med. Chem.
Citation
Wang, C.F., Cui, X.N., Lv, L.X., Wang, W.H., Jing, Q.Q., Yin, J.N., Cao, X.Z., Wei, M.Y., Lu, L., Shao, C.L. (2025) Discovery of Oral Natural Benzofuranoid p-Terphenyl Derivative CHNQD-03301 as a Potent Hypoxia-Inducible Factor-1α Signaling Inhibitor for Cancer Therapy. Journal of medicinal chemistry. :.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping