An in vivo multiplexed small-molecule screening platform

TY - JOUR

T1 - An in vivo multiplexed small-molecule screening platform

AU - Grüner, Barbara M.

AU - Schulze, Christopher J.

AU - Yang, Dian

AU - Ogasawara, Daisuke

AU - Dix, Melissa M.

AU - Rogers, Zoë N.

AU - Chuang, Chen Hua

AU - McFarland, Christopher D.

AU - Chiou, Shin Heng

AU - Brown, J. Mark

AU - Cravatt, Benjamin F.

AU - Bogyo, Matthew

AU - Winslow, Monte M.

N1 - Publisher Copyright: © 2016 Nature America, Inc. All rights reserved.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84987653503

UR - https://www.scopus.com/pages/publications/84987653503#tab=citedBy

U2 - 10.1038/nmeth.3992

DO - 10.1038/nmeth.3992

M3 - Article

C2 - 27617390

SN - 1548-7091

VL - 13

SP - 883

EP - 889

JO - Nature Methods

JF - Nature Methods

IS - 10

ER -