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Published on: July 3, 2013
Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput
Wei Chen1, Minyong Chen, Larry S Barak
1Dept. of Medicine, Duke University Medical Center, Durham, NC 27710, USA. w.chen@duke.edu
Abstract:
Wnt proteins play major roles in development and differentiation, and abnormalities in their regulation are believed to contribute to the formation of many cancers, including colorectal malignancies. As a result, there has been an interest in identifying small molecule inhibitors of Wnt signaling as tool compounds for research or as precursors to new generations of anticancer drugs. Advancements in robotic technology along with reductions in the costs of equipment, chemical libraries, and information handling have made high-throughput drug discovery programs possible in an academic setting. In this minireview we discuss the most plausible protein targets for inhibiting Wnt signaling in colon cancer therapy, list small molecule Wnt inhibitors that have been identified through recent drug discovery efforts, and provide our laboratory's strategy for identifying novel Wnt signaling antagonists using high-throughput screening. In particular, we summarize the results of a screen of over 1,200 drug and druglike compounds we recently completed in which niclosamide was identified as a Wnt pathway antagonist.
Insights
Researchers identified niclosamide as a Wnt pathway antagonist for potential colorectal cancer therapy. High-throughput screening of over 1,200 compounds revealed this promising small molecule inhibitor for Wnt signaling.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Wnt proteins are crucial for cellular development and differentiation.
- Dysregulation of Wnt signaling is implicated in various cancers, notably colorectal malignancies.
- Targeting Wnt signaling is a key strategy for developing novel anticancer therapeutics.
Purpose of the Study:
- To identify small molecule inhibitors of Wnt signaling for research and therapeutic development.
- To discuss potential protein targets for Wnt signaling inhibition in colon cancer.
- To present a laboratory strategy for discovering novel Wnt signaling antagonists via high-throughput screening.
Main Methods:
- High-throughput screening (HTS) of over 1,200 drug and druglike compounds.
- Utilizing advancements in robotic technology and reduced costs for academic drug discovery.
- Reviewing plausible protein targets for Wnt pathway inhibition in colon cancer.
Main Results:
- Niclosamide was identified as a Wnt pathway antagonist from the HTS campaign.
- The study screened a library of over 1,200 compounds for Wnt inhibitory activity.
- Identified potential therapeutic targets and existing small molecule Wnt inhibitors.
Conclusions:
- Niclosamide represents a promising Wnt pathway antagonist for further investigation in colon cancer therapy.
- High-throughput screening is a viable academic strategy for identifying novel Wnt signaling inhibitors.
- Targeting Wnt signaling remains a critical area for developing new anticancer drugs.
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