| Affiliation: | 1. Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy;2. Department for Life Quality Studies, Alma Mater Studiorum – University of Bologna, Rimini, Italy;3. IRCCS, SDN, Naples, Italy;4. Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON, Canada;5. Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY, USA;6. Dipartimento di Biochimica, Biofisica e Patologia generale, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy |
| Abstract: | In recent years there has been a clear consensus that neurodegenerative conditions can be better treated through concurrent modulation of different targets. Herein we report that combined inhibition of transglutaminase 2 (TG2) and histone deacetylases (HDACs) synergistically protects against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2–HDAC binding agents. Compound 3 (E)‐N‐hydroxy‐5‐(3‐(4‐(3‐oxo‐3‐(pyridin‐3‐yl)prop‐1‐en‐1‐yl)phenyl)thioureido)pentanamide] emerged as the most interesting of the series, being able to inhibit TG2 and HDACs both in vitro (TG2 IC50=13.3±1.5 μm , HDAC1 IC50=3.38±0.14 μm , HDAC6 IC50=4.10±0.13 μm ) and in cell‐based assays. Furthermore, compound 3 does not exert any toxic effects in cortical neurons up to 50 μm and protects neurons against toxic insults induced by glutamate (5 mm ) with an EC50 value of 3.7±0.5 μm . |
