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

Manuela Basso, Huan Huan Chen, Debasmita Tripathy, Mariarosaria Conte, Kim Y.P. Apperley, Angela De Simone, Jeffrey W. Keillor, Rajiv Ratan, Angela Nebbioso, Federica Sarno, Lucia Altucci, Andrea Milelli

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)227-230
Number of pages4
JournalChemMedChem
Volume13
Issue number3
DOIs
Publication statusPublished - Feb 6 2018

Keywords

  • histone deacetylase
  • hybrid compounds
  • multiple ligands
  • neurodegeneration
  • transglutaminase 2

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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  • Cite this

    Basso, M., Chen, H. H., Tripathy, D., Conte, M., Apperley, K. Y. P., De Simone, A., Keillor, J. W., Ratan, R., Nebbioso, A., Sarno, F., Altucci, L., & Milelli, A. (2018). Designing Dual Transglutaminase 2/Histone Deacetylase Inhibitors Effective at Halting Neuronal Death. ChemMedChem, 13(3), 227-230. https://doi.org/10.1002/cmdc.201700601