An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/ wingless signaling pathway
Open accessAbstract
Misregulated β-catenin responsive transcription (CRT) has been implicated in the genesis of various malignancies, including colorectal carcinomas, and it is a key therapeutic target in combating various cancers. Despite significant effort, successful clinical implementation of CRT inhibitory therapeutics remains a challenging goal. This is, in part, because of the challenge of identifying inhibitory compounds that specifically modulate the nuclear transcriptional activity of β-catenin while not affecting its cytoskeletal function in stabilizing adherens junctions at the cell membrane. Here, we report an RNAi-based modifier screening strategy for the identification of CRT inhibitors. Our data provide support for the specificity of these inhibitory compounds in antagonizing the transcriptional function of nuclear β-catenin. We show that these inhibitors efficiently block Wnt/β-catenin–induced target genes and phenotypes in various mammalian and cancer cell lines. Importantly, these Wnt inhibitors are specifically cytotoxic to human colon tumor biopsy cultures as well as colon cancer cell lines that exhibit deregulated Wnt signaling.
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Several compounds have been selected as inhibitors targeting β-catenin PPI, including small molecules such as ICG-001, NLs-StAx-h, and CRT inhibitors (iCRT3, iCRT5, iCRT14), Henryin, PKF115-584 and CGP049090.
“In addition, several compounds have been selected as inhibitors targeting β-cateninde PPI, including small molecules such as ICG-001 (176),448 NLs-StAx-h (177)449 and CRT inhibitors (iCRT3 (178), iCRT5 (179), iCRT14 (180)),450 Henryin (181),451 PKF115-584 (182) and CGP049090 (183).452”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [450]
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- Authors
- Gonsalves, F. C., Klein, K., Carson, B. B., Katz, S., Ekas, L. A., Evans, S., Nagourney, R., Cardozo, T., Brown, A. M. C., & DasGupta, R.
- Affiliations
- NYU Langone Health (US)
- Department of Pharmacology and
- Weill Cornell Medicine (US)
- Rational Therapeutics, Long Beach, CA 90806
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-03-10
- Volume
- 108
- Issue
- 15
- Pages
- 5954-5963
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3076864
- OpenAlex
- W2146839729
- Cited by
- 337
- References
- 66
- Citations by year
- 2026: 7 · 2025: 19 · 2024: 18 · 2023: 20 · 2022: 20 · 2021: 34 · 2020: 28 · 2019: 19 · 2018: 22 · 2017: 24 · 2016: 21 · 2015: 27 · 2014: 32 · 2013: 22 · 2012: 17
- FWCI
- 10.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (W81XWH)
- York University
- National Institutes of Health (W81XWH, 1DP2OD002867-01)
- National Cancer Institute (R01CA155125, R01CA123238)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD057525)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- Wnt/β-catenin signaling, β-catenin transcriptional activity, small molecule inhibitors, chemical genetic screen, colorectal cancer, colon cancer cell lines, Wnt target genes, cytotoxicity, adherens junctions
- MeSH terms
- Animals, Antineoplastic Agents, Colonic Neoplasms, Drosophila melanogaster, Drug Screening Assays, Antitumor, Humans, Oxazoles, Transcription, Genetic, Genes, Reporter, Xenograft Model Antitumor Assays, Drosophila Proteins, RNA Interference, Cell Line, Tumor, Wnt Proteins, Wnt1 Protein, beta Catenin, Mice, Small Molecule Libraries, Drug Discovery, High-Throughput Screening Assays
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