Identification and evaluation of soft coral diterpenes as inhibitors of HIF-2α induced gene expression
Related Experiment Video
Updated: Jan 13, 2026
Author Spotlight: Separation of Coral Host Tissues and Algal Symbionts and Analyzing Their Metabolites
Published on: October 13, 2023
Tanja Grkovic1, Emily L Whitson, Daniel C Rabe
1Molecular Targets Laboratory, NCI-Frederick, Frederick, MD 21702, United States.
Abstract:
Kidney cancer was the cause of almost 13,000 deaths in the United States in 2009. Loss of function of the VHL tumor suppressor gene (von Hippel-Lindau disease) dramatically increases the risk of developing clear cell kidney cancer. The VHL protein is best understood for its regulation of hypoxia inducible factor (HIF). HIF responds to changes in oxygen levels in the cell and is responsible for mediating the transcriptional response to hypoxia. Of the three known HIFα gene products, HIF-2α appears to play a fundamental role in renal carcinoma. A high throughput screen was developed to identify small molecule inhibitors of HIF-2 gene expression. The screen was performed and yielded 153 confirmed active natural product extracts. Three of the active extracts were from marine soft corals of the order Alcyonacea: Sarcophyton sp., Lobophytum sarcophytoides and Asterospicularia laurae. Bioassay-guided fractionation led to the isolation of two new cembrane diterpenes, (4Z,8S*,9R*,12E,14E)-9-hydroxy-1-(prop-1-en-2-yl)-8,12-dimethyl-oxabicyclo[9.3.2]-hexadeca-4,12,14-trien-18-one (1), and (1E,3E,7R*,8R*,11E)-1-(2-methoxypropan-2-yl)-4,8,12-trimethyloxabicyclo[12.1.0]-pentadeca-1,3,11-triene (7), as well as eight known compounds, 2-6 and 8-10.
Insights
Scientists screened natural products for kidney cancer inhibitors. Three marine soft coral extracts showed activity, leading to the isolation of novel compounds targeting hypoxia-inducible factor 2 (HIF-2) for potential cancer therapy.
Area of Science:
- Biochemistry
- Natural Products Chemistry
- Oncology
Background:
- Kidney cancer caused nearly 13,000 deaths in the US in 2009.
- Von Hippel-Lindau (VHL) disease, a VHL tumor suppressor gene mutation, significantly elevates clear cell kidney cancer risk.
- The VHL protein regulates hypoxia-inducible factor (HIF), crucial for cellular oxygen level response and hypoxia-mediated transcription.
Purpose of the Study:
- To identify small molecule inhibitors of HIF-2 gene expression.
- To explore natural products as a source for novel anti-cancer compounds.
- To investigate compounds targeting HIF-2, a key factor in renal carcinoma.
Main Methods:
- Development of a high-throughput screen for HIF-2 gene expression inhibitors.
- Screening of natural product extracts.
- Bioassay-guided fractionation of active extracts from marine soft corals.
Main Results:
- The screen identified 153 active natural product extracts.
- Three extracts from marine soft corals (Sarcophyton sp., Lobophytum sarcophytoides, Asterospicularia laurae) were active.
- Isolation of two new cembrane diterpenes and eight known compounds.
Conclusions:
- Marine soft corals are a promising source of novel bioactive compounds.
- Identified compounds may serve as leads for developing HIF-2 inhibitors.
- Further research into these compounds could lead to new kidney cancer therapeutics.
