2026-04-17T02:36:59Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2082552025-12-04T19:31:10Zcom_2072_1057col_2072_478908col_2072_478917col_2072_478933

00925njm 22002777a 4500 dc Barbosa, Bárbara M. G. author Sfyaki, Aikaterini author Rafael, Sergi author José-Duran, Ferran author Pous, Joan author Sánchez Zarzalejo, Carolina author Perez-Lopez, Carles author Vilanova, Mar author Cigler, Marko author Gay i Marín, Marina author Vilaseca Casas, Marta author Winter, Georg E. author Riera i Escalé, Antoni author Mayor-Ruiz, Cristina author 2024-03-01T13:32:00Z 2024-12-27T06:10:09Z 2023-12-28 2024-03-01T13:32:00Z Degraders hold the promise to efficiently inactivate previously intractable disease-relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on the hijacked proteolysis machinery, which can also act as an entry point for resistance. To fully harness the potential of targeted protein degradation, it is crucial to comprehend resistance mechanisms and formulate effective strategies to overcome them. We conducted a chemical screening to identify synthetic lethal vulnerabilities of cancer cells that exhibit widespread resistance to degraders. Comparative profiling followed by tailored optimization delivered the small molecule RBS-10, which shows preferential cytotoxicity against cells pan-resistant to degraders. Multiomics deconvolution of the mechanism of action revealed that RBS-10 acts as a prodrug bioactivated by the oxidoreductase enzyme NQO1, which is highly overexpressed in our resistance models. Collectively, our work informs on NQO1 as an actionable vulnerability to overcome resistance to degraders and as a biomarker to selectively exploit bioactivatable prodrugs in cancer. Proteïnes Cèl·lules canceroses Proteins Cancer cells Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.