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Updated: Jul 14, 2026
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Analysis of the c-KIT Ligand Promoter Using Chromatin Immunoprecipitation
Published on: June 27, 2017
Natural products active in aberrant c-Kit signaling
Curtis J Henrich1, Ekaterina I Goncharova, Jennifer A Wilson
1Molecular Targets Development Program, NCI-Frederick, Frederick, MD 21702, USA. henrichc@ncifcrf.gov
Chemical Biology & Drug Design
|June 2, 2007
Summary
Developing drugs targeting mutated c-Kit is challenging. Researchers created a new assay to find compounds that kill cancer cells with active c-Kit, identifying two natural products that affect mitochondrial potential.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Targeting constitutively active kinase domain mutants of c-Kit is difficult.
- Aberrant c-Kit signaling is implicated in various cancers.
- Novel therapeutic strategies are needed to address these challenges.
Purpose of the Study:
- To develop a high-throughput screening assay for identifying compounds that selectively kill cells with active c-Kit.
- To discover novel natural products with differential cytotoxicity against cells expressing c-Kit mutants.
- To investigate the mechanism of action of identified compounds.
Main Methods:
- Development of a high-throughput differential cytotoxicity assay using murine IC2 mast cells expressing wild type or mutant c-Kit (D814Y).
- Screening of natural product extract libraries followed by assay-guided fractionation.
- Testing of identified compounds against a panel of 73 signaling enzymes and assessment of mitochondrial potential.
Main Results:
- Two differentially active natural products were identified using the developed assay.
- The identified compounds did not inhibit the tested signaling enzymes, including wild type and mutant c-Kit.
- Commercially available inhibitors failed to replicate the differential activity observed with the natural products.
- Both compounds were found to affect mitochondrial potential in cells expressing the c-Kit D814Y mutation.
Conclusions:
- The novel high-throughput assay is effective for discovering compounds targeting constitutively active c-Kit.
- The identified natural products represent a new class of compounds with a unique mechanism of action.
- These natural products may offer new therapeutic avenues for aberrant c-Kit signaling pathways in cancer.
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