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| Autores principales: | , , , , , , , , , , , , , |
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| Formato: | Artículo Open Access |
| Publicado: |
Wiley
2026
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| Materias: | |
| Acceso en línea: | https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.70305 |
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- Identification of 2‐Substituted‐3‐Hydroxy‐2,3‐Dihydroquinazolin‐4(1 H ) Ones as Cell‐Active Inhibitors of KDM4A Lysine Demethylase Alessandra Feoli Amodio Luca Balzano Ida Pacilio Alessandra Cipriano Roman Belle Giacomo Pepe Manuela Giovanna Basilicata Pietro Campiglia Fabrizio Micheli Akane Kawamura Ciro Milite Sabrina Castellano Axel Imhof Gianluca Sbardella ChemMedChem Lysine demethylases of the KDM4 subfamily are epigenetic regulators frequently dysregulated in cancer, yet the identification of cell‐active inhibitors remains challenging due to assay interference and limited chemotype diversity. Here, we report the discovery of 2‐substituted‐3‐hydroxy‐2,3‐dihydroquinazolin‐4(1 H )‐ones as a new class of KDM4A inhibitors. A focused library was identified through a screening cascade integrating biochemical, biophysical, and mass spectrometry–based assays to minimize false positives. Orthogonal validation using surface plasmon resonance, nanodifferential scanning fluorimetry, and MALDI‐TOF‐MS enabled reliable compound prioritization, leading to the identification of compound 6i as a validated KDM4A binder and inhibitor. Cellular target engagement was demonstrated by quantitative label‐free proteomics, revealing a dose‐dependent accumulation of H3K9me2 and H3K9me3 in HEK293T cells, consistent with on‐target inhibition of KDM4‐family demethylases. Compound 6i further exhibited favorable solubility, permeability, and metabolic stability, supporting its qualification as a promising cell‐active KDM4 inhibitor scaffold. 10.1002/cmdc.70305 http://creativecommons.org/licenses/by/4.0/