# Nanodroplet Array Platform for Integrated Synthesis and Screening of MEK Inhibitors: a Miniaturized Approach to Early Drug Discovery

## TL;DR

A miniaturized platform enables fast and cost-effective drug discovery by combining synthesis and screening of MEK inhibitors in tiny droplets.

## Contribution

A nanodroplet array platform integrates synthesis, characterization, and cell-based screening of MEK inhibitors in a miniaturized format.

## Key findings

- 46 compounds showed higher cytotoxicity than the approved MEK inhibitor mirdametinib.
- Molecular docking revealed a shared allosteric binding mechanism among active compounds.
- The platform synthesized and screened 325 compounds in 7 days using minimal resources.

## Abstract

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.

We present a nanodroplet array platform that integrates solid‐phase synthesis, MALDI‐MS analysis, and cell‐based screening. Using nanoliter droplets, we synthesized and tested 325 potential MEK inhibitors and identified 46 active compounds. This miniaturized approach combines chemistry and biology on a single chip, reducing time, cost, and material use in early‐stage drug discovery.