1. Academic Validation
  2. An in vivo multiplexed small-molecule screening platform

An in vivo multiplexed small-molecule screening platform

  • Nat Methods. 2016 Oct;13(10):883-889. doi: 10.1038/nmeth.3992.
Barbara M Grüner # 1 Christopher J Schulze # 2 Dian Yang 3 Daisuke Ogasawara 4 Melissa M Dix 4 Zoë N Rogers 1 Chen-Hua Chuang 1 Christopher D McFarland 5 Shin-Heng Chiou 1 J Mark Brown 6 Benjamin F Cravatt 4 Matthew Bogyo 2 7 3 8 Monte M Winslow 1 2 3 8
Affiliations

Affiliations

  • 1 Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • 2 Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 3 Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
  • 4 Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
  • 5 Department of Biology, Stanford University, Stanford, CA, USA.
  • 6 Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
  • 7 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
  • 8 Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • # Contributed equally.
Abstract

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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