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

Journal Article
Basso M, Chen HH, Tripathy D, Conte M, Apperley KYP, De Simone A, Keillor JW, Ratan R, Nebbioso A, Sarno F, Altucci L, Milelli A.
Year Published: 
ChemMedChem. 2018 Feb 6;13(3):227-230. doi: 10.1002/cmdc.201700601. Epub 2018 Jan 18.
PMID: 29286587 DOI: 10.1002/cmdc.201700601
Abstract on PubMed


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.


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