Screening and Identification of Hypoxia-Inducible Factor Signaling Inhibitor with Antiangiogenic Activity

Chao Li; Yuanzheng Wei; Ping Wang; Xiaoxian Xue; Guangyao Wei; Mu Chen; Xinyun Zhang; Lei Cai; Yu Zhang; Xumu Zhang; Yingjun Li

doi:10.1055/s-0044-1796627

Pharmaceutical Fronts, Inhaltsverzeichnis

CC BY 4.0 · Pharmaceutical Fronts 2024; 06(04): e421-e429
DOI: 10.1055/s-0044-1796627

Original Article

Screening and Identification of Hypoxia-Inducible Factor Signaling Inhibitor with Antiangiogenic Activity

Chao Li^#

¹Department of Chemistry and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, People's Republic of China

,

Yuanzheng Wei^#

²Guangdong Province Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong, People's Republic of China

,

Ping Wang^#

¹Department of Chemistry and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, People's Republic of China

,

Xiaoxian Xue

¹Department of Chemistry and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, People's Republic of China

,

Guangyao Wei

³Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China

,

Mu Chen

⁴Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China

,

Xinyun Zhang

⁵ICE Bioscience Incorporated Company, Beijing, People's Republic of China

,

Lei Cai

²Guangdong Province Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong, People's Republic of China

,

Yu Zhang

²Guangdong Province Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong, People's Republic of China

,

Xumu Zhang

¹Department of Chemistry and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, People's Republic of China

,

Yingjun Li

¹Department of Chemistry and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, People's Republic of China

⁶State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, People's Republic of China

› Institutsangaben

Abstract

Hypoxia-inducible factors (HIFs) play a key role in regulating cellular responses to low-oxygen conditions, particularly in promoting angiogenesis in tumor microenvironments. Aberrant HIF signaling enhances tumor growth and contributes to resistance against chemotherapy and radiotherapy. Targeting the HIF pathway has emerged as a promising strategy for cancer therapy. This study aimed to identify novel inhibitors of HIF signaling and evaluate their potential against the HIF–vascular endothelial growth factor (VEGF) axis for antiangiogenic therapy. In screening our in-house drug library using hypoxia response element dual-luciferase assay, HST3782, a novel 3-hydroxy-8-azabicyclo[3.2.1]octane-bridged compound, was identified as a promising HIF inhibitor, with IC₅₀ of 1.028 μmol/L. In this work, the inhibitory effect of HST3782 on HIF signaling was confirmed in triple-negative breast cancer cells (SUM159) under hypoxic conditions (1% O₂). Quantitative real-time polymerase chain reaction suggested the inhibitory effect of HST3782 on the expression of angiogenic genes, including VEGFa, VEGFR-1, BNIP3, and SERPINE1 in 786-O cells. Zebrafish model testing revealed that HST3782 inhibited intersegmental and subintestinal vessel development by up to 56% without marked toxicity. HST3782 was synthesized through a two-step 1,2,4 triazole cyclization reaction, followed by amide formation and ketone reduction steps. The last step of hydrogenation with sodium borohydride yielded a pair of endo-exo isomers. 2D-NOESY (Nuclear Overhauser effect spectroscopy) analysis confirmed that the compound's endo isomer (HST3782) had superior inhibitory effects relative to its exo form (8b). Given the above, HST3782 is a novel HIF inhibitor, with strong antiangiogenic effects and presents a valuable scaffold for future development of antiangiogenic drugs targeting the HIF–VEGF axis. Further studies are warranted to optimize HST3782's pharmacokinetics and therapeutic efficacy for antiangiogenic therapy in hypoxia-related malignancies.

Keywords

hypoxia-inducible factor - HIF pathway inhibitor - angiogenesis - zebrafish - bridged compound

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Referenzen

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