An in vivo multiplexed small-molecule screening platform

作者：Gruner Barbara M; Schulze Christopher J; Yang Dian; Ogasawara Daisuke; Dix Melissa M; Rogers Zoe N; Chuang Chen Hua; McFarland Christopher D; Chiou Shin Heng; Brown J Mark; Cravatt Benjamin F; Bogyo Matthew^*; Winslow Monte M^*

来源：Nature Methods, 2016, 13(10): 883-+.

DOI：10.1038/nmeth.3992

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 ABHDHD6. 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.

• 出版日期2016-10