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Updated: May 3, 2026
Co-immunoprecipitation Assay Using Endogenous Nuclear Proteins from Cells Cultured Under Hypoxic Conditions
Published on: August 2, 2018
A perylene derivative regulates HIF-1α and Stat3 signaling pathways
Han Chen1, Yongli Guan2, Gu Yuan3
1Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Abstract:
It is becoming increasingly evident that improving the cure rate of many cancers will require treatment regimens hit more than one validated tumor targets. Developing an anti-cancer agent that targets two oncoproteins simultaneously is a promising strategy for accomplishing this goal. It would be expected to promote drug efficacy, reduce therapy-resistant without introducing additional toxic side effects. HIF-1α is a key regulator of the cellular response to hypoxia and is involved in tumor angiogenesis and cancer cell survival, glucose metabolism, and invasion. Stat3 has several oncogenic functions, including suppression of anti-tumor immune responses and promotion of inflammation. Recently, we have identified the perylene derivative, TEL03, as a dual inhibitor that targets both HIF-1α and Stat3. TEL03 blocks the expression of both HIF-1α and Stat3, regulated oncogenes (e.g., Bcl-2, VEGF, Glut1, and others) in cancer cells, and induces cancer cell apoptosis. The results demonstrated that: (i) TEL03 blocks Stat3 phosphorylation, and inhibits Stat3 transcriptional activity; and (ii) interferes the binding of HIF-1α to p300/CBP inducing its degradation by proteasomes under hypoxic conditions. Our in vivo tests showed that as a dual inhibitor, TEL03 dramatically inhibited tumor growth, and provided the evidence that targeting both HIF-1α and Stat3 simultaneously could be a promising strategy for breast and pancreatic cancer therapies.
Insights
A novel dual inhibitor, TEL03, effectively targets both HIF-1α and Stat3, crucial in cancer progression. This dual-action approach shows promise for enhancing anti-cancer efficacy and overcoming resistance in breast and pancreatic cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Improving cancer cure rates necessitates targeting multiple validated tumor targets simultaneously.
- Hypoxia-inducible factor 1-alpha (HIF-1α) and Signal transducer and activator of transcription 3 (Stat3) are key oncogenic proteins involved in tumor growth, survival, and immune evasion.
- Developing dual-acting anti-cancer agents offers a strategy to enhance efficacy and reduce resistance without increasing toxicity.
Purpose of the Study:
- To identify and characterize a novel dual inhibitor targeting both HIF-1α and Stat3.
- To evaluate the anti-cancer effects of the identified compound, TEL03, in preclinical models.
Main Methods:
- Identification of perylene derivative TEL03 as a dual inhibitor of HIF-1α and Stat3.
- Assessment of TEL03's effects on Stat3 phosphorylation and transcriptional activity.
- Investigation of TEL03's impact on HIF-1α binding to p300/CBP and subsequent proteasomal degradation under hypoxic conditions.
- Evaluation of TEL03's efficacy in inhibiting tumor growth in vivo.
Main Results:
- TEL03 effectively blocks Stat3 phosphorylation and inhibits its transcriptional activity.
- TEL03 interferes with HIF-1α binding to p300/CBP, leading to HIF-1α degradation under hypoxia.
- TEL03 downregulates oncogenic targets regulated by HIF-1α and Stat3, including Bcl-2, VEGF, and Glut1.
- In vivo studies demonstrated that TEL03 significantly inhibited tumor growth.
Conclusions:
- Simultaneous targeting of HIF-1α and Stat3 with TEL03 is a promising therapeutic strategy.
- TEL03 demonstrates significant anti-tumor activity, inducing cancer cell apoptosis and inhibiting tumor growth.
- This dual-inhibition approach holds potential for the treatment of breast and pancreatic cancers.
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