Just-in-Time Compound Pooling Increases Primary Screening Capacity without Compromising Screening Quality.
Compound pooling, or multiplexing more than one compound per well during primary high-throughput screening (HTS), is a controversial approach with a long history of limited success. Many issues with this approach likely arise from long-term storage of library plates containing complex mixtures of compounds at high concentrations. Due to the historical difficulties with using multiplexed library plates, primary HTS often uses a one-compound-one-well approach. However, as compound collections grow, innovative strategies are required to increase the capacity of primary screening campaigns. Toward this goal, we have developed a novel compound pooling method that increases screening capacity without compromising data quality. This method circumvents issues related to the long-term storage of complex compound mixtures by using acoustic dispensing to enable "just-in-time" compound pooling directly in the assay well immediately prior to assay. Using this method, we can pool two compounds per well, effectively doubling the capacity of a primary screen. Here, we present data from pilot studies using just-in-time pooling, as well as data from a large >2-million-compound screen using this approach. These data suggest that, for many targets, this method can be used to vastly increase screening capacity without significant reduction in the ability to detect screening hits.
Department of Lead Discovery & Optimization, Bristol-Myers Squibb, Wallingford, CT, USA lisa.elkin@bms.com.
L L
LL
Elkin
Department of Lead Discovery & Optimization, Bristol-Myers Squibb, Wallingford, CT, USA.
D G
DG
Harden
Forma Therapeutics, Watertown, MA, USA.
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S
Saldanha
Department of Lead Discovery & Optimization, Bristol-Myers Squibb, Wallingford, CT, USA.
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H
Ferguson
Department of Molecular Structure & Design, Bristol-Myers Squibb, Pennington, NJ, USA.
D L
DL
Cheney
Department of Molecular Structure & Design, Bristol-Myers Squibb, Pennington, NJ, USA.
S N
SN
Pieniazek
Department of Lead Discovery & Optimization, Bristol-Myers Squibb, Wallingford, CT, USA.
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DP
Maloney
Department of Lead Discovery & Optimization, Bristol-Myers Squibb, Wallingford, CT, USA.
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J
Zewinski
Forma Therapeutics, Watertown, MA, USA.
J
J
O'Connell
Department of Lead Discovery & Optimization, Bristol-Myers Squibb, Wallingford, CT, USA.
M
M
Banks
D055808:Drug Discovery / Q000379:methods* / Q000592:standards; D057166:High-Throughput Screening Assays; D010865:Pilot Projects; D015203:Reproducibility of Results; D054852:Small Molecule Libraries
D054852:Small Molecule Libraries
acoustic dispensing; compound multiplexing; compound pooling; high-throughput screening (HTS)