An in vivo multiplexed small-molecule screening platform
Open accessAbstract
Phenotype-based small-molecule screening is a powerful method to identify molecules that regulate cellular functions. However, such screens are generally performed in vitro under conditions that do not necessarily model complex physiological conditions or disease states. Here, we use molecular cell barcoding to enable direct in vivo phenotypic screening of small-molecule libraries. The multiplexed nature of this approach allows rapid in vivo analysis of hundreds to thousands of compounds. Using this platform, we screened >700 covalent inhibitors directed toward hydrolases for their effect on pancreatic cancer metastatic seeding. We identified multiple hits and confirmed the relevant target of one compound as the lipase ABHD6. Pharmacological and genetic studies confirmed the role of this enzyme as a regulator of metastatic fitness. Our results highlight the applicability of this multiplexed screening platform for investigating complex processes in vivo.
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A multiplexed in vivo screening platform was developed in which barcoded pancreatic ductal adenocarcinoma lines were pretreated with electrophilic compounds and injected into mice to observe compound-dependent decrease in metastatic potential.
“a multiplexed in vivo screening platform was developed in which barcoded pancreatic ductal adenocarcinoma lines were pretreated with electrophilic compounds and injected into mice to observe the compound-dependent decrease in metastatic potential186.”
From Advances in covalent drug discovery (2022) · cites this paper as [186]
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Advances in covalent drug discovery
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- Authors
- Grüner, B. M., Schulze, C. J., Yang, D., Ogasawara, D., Dix, M. M., Rogers, Z. N., Chuang, C.-H., McFarland, C. D., Chiou, S.-H., Brown, J. M., Cravatt, B. F., Bogyo, M., & Winslow, M. M.
- Affiliations
- Stanford Medicine (US)
- Scripps Research Institute (US)
- Stanford University (US)
- Cleveland Clinic (US)
- Corresponding author
- Bogyo, Matthew
- Winslow, Monte M
- ORCID
- Venue
- Nature Methods
- Published
- 2016-09-12
- Volume
- 13
- Issue
- 10
- Pages
- 883-889
- ISSN
- 1548-7091 (ISSN-L)
- 1548-7105
- PMC
- PMC5088491
- OpenAlex
- W2519825823
- Cited by
- 62
- References
- 49
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 10 · 2021: 13 · 2020: 6 · 2019: 8 · 2018: 6 · 2017: 4
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Methods (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL122283)
- National Institute on Drug Abuse (R01DA033760)
- National Cancer Institute (R21CA188863, R25CA180993, F32CA200078, R01CA132630, P30CA124435)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Keywords
- phenotypic screening, metastatic seeding, pancreatic cancer metastasis, ABHD6, lipase
- MeSH terms
- Animals, Cell Adhesion, Cell Movement, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Humans, Liver Neoplasms, Monoacylglycerol Lipases, Neoplasm Transplantation, Pancreatic Neoplasms, Mice, SCID, Cell Line, Tumor, Cell Proliferation, Mice, Small Molecule Libraries, Gene Knockdown Techniques, Molecular Imaging, High-Throughput Screening Assays
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