<i>In vitro</i> screening of compounds for targeting gastric cancer with Y220C p53 mutation: a molecule combining zinc chelation and a Michael acceptor drives <i>CDKN1</i> and <i>BBC3</i> expression to restore a p53-dependent cytotoxicity
approach, four compounds (AG1, AG2, AG3, and RK349) were screened for potential reactivation of p53-Y220C in GC cells. AG3, a compound with zinc chelation and Michael acceptor properties, was found to induce p53 target gene expression via p53-dependent and -independent pathways. AG3 limited reactive oxygen species production, reducing toxicity to healthy cells. Furthermore, AG3 induced p53-dependent cytotoxicity and enhanced chemotherapy response. This study presents a novel compound with p53-Y220C reactivation potential, highlighting its promise for further development.
Authors
- Andrew McGown (ORCID: https://orcid.org/0000-0002-2187-3850)
- Amanda Jarvis
- Simon Peschard (ORCID: https://orcid.org/0000-0002-8207-6724)
- Ruxandra Moraru (ORCID: https://orcid.org/0000-0002-7210-8665)
- Christian Gaiddon (ORCID: https://orcid.org/0000-0003-4315-3851)
- Christophe Orvain (ORCID: https://orcid.org/0000-0001-6998-7315)
- Simon Nannini (ORCID: https://orcid.org/0000-0003-3097-727X)
- Csilla Kállay (ORCID: https://orcid.org/0000-0002-3910-2499)
- Georg Mellitzer (ORCID: https://orcid.org/0000-0003-4467-0789)
- Andreas C. Joerger (ORCID: https://orcid.org/0000-0002-1232-0138)
- Sebastian Mandel (ORCID: https://orcid.org/0009-0003-8281-1498)
- Antal Galvácsi (ORCID: https://orcid.org/0009-0004-9672-0850)
- Celine Sieffert
- Xin-Yue Gao
- Matthias G. Baud
- Isabelle Gross
- Georges E. Kostakis
- John Spencer
- Audrey Nion
- Dimitros-Ilias Balourdas
- Sophie Lottiaux
Institutions
- Goethe University Frankfurt (DE)
- University of Debrecen (HU)
- University of Sussex (GB)
- Discovery Centre (CA)
- Structural Genomics Consortium (CA)
- University of Southampton (GB)
- Université de Strasbourg (FR)
- University of Edinburgh (GB)
Publication Details
- Journal
- Journal of Enzyme Inhibition and Medicinal Chemistry
- Published
- 2026-05-21
- DOI
- https://doi.org/10.1080/14756366.2026.2638836
- Primary Topic
- Cancer-related Molecular Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Ligue Contre le Cancer
- Structural Genomics Consortium