Designing Novel Dual Transglutaminase 2 / Histone Deacetylase Inhibitors Effective in Halting Neuronal Death

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) protects synergistically 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 emerges 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 assay. 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 of 3.7 ± 0.5 µM.