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Published on: November 9, 2020
Design, synthesis and biological evaluation of novel HIF-1α PROTACs degrader as potent anti-cervical cancer agents
En-Jie Zhu1, Xing-Sheng Bu2, Ying Yue3
1CAS Key Laboratory of Chemistry of Northwestern Plant Resources and Key Laboratory for Natural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Lanzhou 730000, People's Republic of China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
Abstract:
Cervical cancer is the fourth most common and deadly cancer globally. Hypoxia-inducible factor-1α (HIF-1α) plays a key promoter of tumor progression and treatment resistance, making it an important anticancer target. Here, we designed and synthesized a series of novel HIF-1α-targeting PROTAC degraders based on LW-6 and its derivative W-1. Among them, Z12 showed the strongest anti-proliferative and HIF1α degradation activities in HeLa cells. Z12 promoted HIF-1α degradation via the ubiquitin-proteasome pathway by facilitating the formation of a HIF-1α/VHL ternary complex. Furthermore, Z12 inhibited HeLa cell proliferation, migration, and colony formation, induced apoptosis, and reduced p-MEK and p-AKT expression in the MAPK and PI3K/AKT pathways. This work offers a promising strategy for developing HIF1α-PROTAC degraders and treating cervical cancer.
Insights
Researchers developed novel PROTAC degraders targeting hypoxia-inducible factor-1α (HIF-1α) for cervical cancer. Z12 demonstrated potent anti-cancer effects by degrading HIF-1α and inhibiting tumor cell growth.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Cervical cancer is a major global health challenge.
- Hypoxia-inducible factor-1α (HIF-1α) is a critical driver of tumor progression and treatment resistance in cervical cancer.
- Targeting HIF-1α presents a promising therapeutic strategy.
Purpose of the Study:
- To design and synthesize novel Proteolysis-Targeting Chimeras (PROTACs) that degrade HIF-1α.
- To evaluate the efficacy of these PROTACs in cervical cancer models.
- To investigate the molecular mechanisms underlying their anti-cancer activity.
Main Methods:
- Synthesis of novel HIF-1α-targeting PROTAC degraders based on LW-6 and W-1.
- Assessment of anti-proliferative and HIF-1α degradation activities in HeLa cells.
- Investigation of the ubiquitin-proteasome pathway and ternary complex formation (HIF-1α/VHL).
- Evaluation of effects on cell proliferation, migration, colony formation, apoptosis, and key signaling pathways (MAPK, PI3K/AKT).
Main Results:
- Compound Z12 exhibited the most potent HIF-1α degradation and anti-proliferative effects in HeLa cells.
- Z12 induced HIF-1α degradation via the ubiquitin-proteasome pathway by promoting HIF-1α/VHL complex formation.
- Z12 significantly inhibited HeLa cell proliferation, migration, and colony formation, induced apoptosis, and reduced p-MEK and p-AKT levels.
Conclusions:
- Novel HIF-1α-PROTAC degraders, particularly Z12, show significant potential for cervical cancer treatment.
- Z12 effectively targets HIF-1α and exerts broad anti-cancer effects.
- This study provides a promising strategy for developing HIF-1α-targeted therapies for cervical cancer.
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