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.

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

Angela De Simone;
2018-01-01

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.
2018
13
3
227
230
http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201700601/epdf
histone deacetylase · hybrid compounds · multipleligands · neurodege neration · transglutaminase 2
Manuela Basso; Huan Huan Chen; Debasmita Tripathy; Mariarosaria Conte; Kim Y. P. Apperley; Angela De Simone; Jeffrey W. Keillor; Rajiv Ratan; Angela N...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1719629
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