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Designing Dual Transglutaminase 2/Histone Deacetylase Inhibitors Effective at Halting Neuronal Death
Author(s) -
Basso Manuela,
Chen Huan Huan,
Tripathy Debasmita,
Conte Mariarosaria,
Apperley Kim Y. P.,
De Simone Angela,
Keillor Jeffrey W.,
Ratan Rajiv,
Nebbioso Angela,
Sarno Federica,
Altucci Lucia,
Milelli Andrea
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700601
Subject(s) - hdac6 , hdac1 , histone deacetylase , tissue transglutaminase , glutamate receptor , chemistry , histone deacetylase 2 , in vitro , hdac11 , hdac10 , pharmacology , biochemistry , histone , microbiology and biotechnology , enzyme , biology , receptor , gene
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 IC 50 =13.3±1.5 μ m , HDAC1 IC 50 =3.38±0.14 μ m , HDAC6 IC 50 =4.10±0.13 μ m ) and in cell‐based assays. Furthermore, compound 3 does not exert any toxic effects in cortical neurons up to 50 μ m and protects neurons against toxic insults induced by glutamate (5 m m ) with an EC 50 value of 3.7±0.5 μ m .