Continuing the research aimed at discovering new BAG3 modulators as attractive anticancer drug candidates, a screening campaign on an in-house library is performed, including compounds featuring a large variety of scaffolds. The obtained results prompted a focus on the triazole moiety and, following a stepwise structural refinement of this scaffold guided by biophysical assays and computational studies, a very attractive compound (2) is identified showing a tight interaction with BAG3 and displaying a significant cytotoxic activity. The discovery of compound 2, whose effects on apoptosis and proteostasis confirm the disruption of BAG3-related pathways, is particularly relevant given the limited number of BAG3 modulators reported so far. Moreover, the computational data highlight the potential to further explore the triazole scaffold for the development of more potent anticancer agents.

Department of Pharmacy University of Salerno Via Giovanni Paolo 2 132 84084 Fisciano Italy

Faculty of Medicine and Dentistry and Czech Advanced Technology and Research Institute Institute of Molecular and Translational Medicine Palackу University in Olomouc Krížkovského 511 8 779 00 Olomouc Czech Republic

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