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We developed a microarray-based system for screening small molecules in mammalian cells. This system is compatible with image-based screens and requires fewer than 100 cells per compound. Each compound is impregnated in a 200-microm-diameter disc composed of biodegradable poly-(D),(L)-lactide/glycolide copolymer. Cells are seeded on top of these discs, and compounds slowly diffuse out, affecting proximal cells. In contrast with microtiter-based screening, this system does not involve the use of wells or walls between each compound-treated group of cells. We demonstrate detection of the effects of a single compound in a large microarray, that diverse compounds can be released in this format, and that extended release over several days is feasible. We performed a small synthetic lethal screen and identified a compound (macbecin II) that has reduced activity in cells with RNA interference-mediated decrease in the expression of tuberous sclerosis 2. Thus, we have developed a microarray-based screening system for testing the effects of small molecules on mammalian cells by using an imaging-based readout. This method will be useful to those performing small-molecule screens to discover new chemical tools and potential therapeutic agents.

Microarrays of small molecules embedded in biodegradable polymers for use in mammalian cell-based screens