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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| Hauptverfasser: | , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
November 24, 2025
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| In: |
Angewandte Chemie. International edition
Year: 2025, Jahrgang: 64, Heft: 48, Pages: 1-16 |
| ISSN: | 1521-3773 |
| DOI: | 10.1002/anie.202507586 |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a Nanodroplet array platform for integrated synthesis and screening of MEK inhibitors |b a miniaturized approach to early drug discovery |c 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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| 520 | |a 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. | ||
| 650 | 4 | |a high-throughput | |
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| 700 | 1 | |a Höpfner, Julius |e VerfasserIn |4 aut | |
| 700 | 1 | |a Bauer, Liana |e VerfasserIn |4 aut | |
| 700 | 1 | |a Varadharajan, Divya |e VerfasserIn |4 aut | |
| 700 | 1 | |a Schmidt, Stefan |e VerfasserIn |4 aut | |
| 700 | 1 | |a Fröhlich, Björn |e VerfasserIn |4 aut | |
| 700 | 1 | |a Wellenhofer, Benjamin |e VerfasserIn |4 aut | |
| 700 | 1 | |a Luchena, Charlotte |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Popova, Anna A. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Levkin, Pavel A. |e VerfasserIn |4 aut | |
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