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Nanodroplet array platform for integrated synthesis and screening of MEK inhibitors: a miniaturized approach to early drug discovery

Early-stage drug discovery relies on high-throughput screenings, which are costly and time-intensive, limiting access for academic laboratories and small companies. A key bottleneck is the lack of miniaturization and the separation of compound synthesis from screening. We present a nanoliter droplet...

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Main Authors: Seifermann, Maximilian (Author) , Höpfner, Julius (Author) , Bauer, Liana (Author) , Varadharajan, Divya (Author) , Schmidt, Stefan (Author) , Fröhlich, Björn (Author) , Wellenhofer, Benjamin (Author) , Luchena, Charlotte (Author) , Hopf, Carsten (Author) , Popova, Anna A. (Author) , Levkin, Pavel A. (Author)
Format: Article (Journal)
Language:English
Published: November 24, 2025
In: Angewandte Chemie. International edition
Year: 2025, Volume: 64, Issue: 48, Pages: 1-16
ISSN:1521-3773
DOI:10.1002/anie.202507586
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/anie.202507586
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202507586
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Author Notes:Maximilian Seifermann, Julius Höpfner, Liana Bauer, Divya Varadharajan, Stefan Schmidt, Björn Fröhlich, Benjamin Wellenhofer, Charlotte Luchena, Carsten Hopf, Anna A. Popova, and Pavel A. Levkin
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Summary:Early-stage drug discovery relies on high-throughput screenings, which are costly and time-intensive, limiting access for academic laboratories and small companies. A key bottleneck is the lack of miniaturization and the separation of compound synthesis from screening. We present a nanoliter droplet array platform integrating synthesis, characterization, and cell-based screening of 325 MEK (mitogen-activated protein kinase kinase) inhibitors, targeting the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathway, implicated in colorectal and pancreatic cancer. The platform enables on-chip synthesis, MALDI-MSI (matrix-assisted laser desorption/ionization-mass spectrometry imaging) characterization, and cell-based screening within 200 nL droplets containing 20 nmol starting material (∼4 ng final compound), and only 300 cells per droplet. Screening identified 46 compounds with higher cytotoxicity than mirdametinib, a clinically approved MEK inhibitor. Molecular docking revealed a shared allosteric binding mechanism, indicating non-competitive ATP inhibition. Synthesis and screening of all 325 compounds were completed within 7 days, requiring <10 mg of reactants, <250 µL solvent, and ∼100 µL of cell suspension (∼100,000 cells in total). Our results demonstrate that integrating miniaturized combinatorial synthesis and biological screening in a single platform can accelerate early-stage drug discovery while reducing cost and resource use.
Item Description:Zuerst veröffentlicht: 18. August 2025
Gesehen am 14.01.2026
Physical Description:Online Resource
ISSN:1521-3773
DOI:10.1002/anie.202507586

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