High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines

Yu, Channing; Mannan, Aristotle M.; Yvone, Griselda M.; Ross, Kenneth N.; Zhang, Yan Ling; Marton, Melissa A.; Taylor, Bradley R.; Crenshaw, Andrew; Gould, Joshua; Tamayo, Pablo; Weir, Barbara A.; Tsherniak, Aviad; Wong, Bang; Garraway, Levi A.; Shamji, Alykhan F.; Palmer, Michelle; Foley, Michael A.; Winckler, Wendy; Schreiber, Stuart L.; Kung, Andrew L.; Golub, Todd R.

doi:10.1038/nbt.3460

Cited by 288 publications

(333 citation statements)

References 25 publications

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“…Our findings suggest that DOS-derived compound collections, which comprise three-dimensional structures reminiscent of natural products that have yielded many small-molecule probes of diverse mammalian processes 41,42 , are also a rich resource for identifying targets and readily optimized chemical scaffolds to supplement the current antimalarial pipeline.…”

Section: Discussionmentioning

confidence: 95%

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors

Kato

Comer

Sakata‐Kato

et al. 2016

Nature

234

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Antimalarial drugs have thus far been chiefly derived from two sources—natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.

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Section: Discussionmentioning

confidence: 95%

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors

Kato

Comer

Sakata‐Kato

et al. 2016

Nature

234

237

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“…), 64 and an imperfect concordance between different types of biomolecules (e.g., mRNA transcripts and the corresponding translated proteins). 65 Other types of data, such as chemical modifications, enzymatic activities, and genotypes, can also be integrated as additional inputs for a multilayered omics characterization, 66–68 adding valuable information but also increasing the complexity of analysis.…”

Section: Big Data-driven Techniques For Drug Discoverymentioning

confidence: 99%

Using Big Data to Discover Diagnostics and Therapeutics for Gastrointestinal and Liver Diseases

et al. 2017

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Technologies such as genome sequencing, gene expression profiling, proteomic and metabolomic analyses, electronic medical records, and patient-reported health information have produced large amounts of data, from various populations, cell types, and disorders (big data). However, these data must be integrated and analyzed if they are to produce models or concepts about physiologic function or mechanisms of pathogenesis. Many of these data are available to the public, allowing researchers anywhere to search for markers of specific biologic processes or therapeutic targets for specific diseases or patient types. We review recent advances in the fields of computational and systems biology, and highlight opportunities for researchers to use big data sets in the fields of gastroenterology and hepatology, to complement traditional means of diagnostic and therapeutic discovery.

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“…We employed molecular barcoding combined with high-throughput sequencing to perform multiplexed analysis of compound pretreated cells. Molecular barcoding of cells has been used to track diverse sub-clones of cancer cells and hematopoietic stem cells in vivo as well as to monitor responses to chemotherapy in vitro and in vivo 8-13 . This technique is particularly suited to our screening approach, as it allows quantification of differentially pretreated populations in vivo .…”

Section: Introductionmentioning

confidence: 99%

An in vivo multiplexed small-molecule screening platform

et al. 2016

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Phenotype-based small molecule screening is a powerful method to identify regulators of cellular function. However, such screens are generally performed in vitro using 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 libraries of small molecules. 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 towards 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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High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines

Cited by 288 publications

References 25 publications

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors

Using Big Data to Discover Diagnostics and Therapeutics for Gastrointestinal and Liver Diseases

An in vivo multiplexed small-molecule screening platform

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