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

Area of Science:

• Neuroscience
• Pharmacology
• Medicinal Chemistry

Background:

• Neurodegenerative diseases necessitate multi-target therapeutic strategies.
• Combined inhibition of transglutaminase 2 (TG2) and histone deacetylases (HDACs) shows synergistic neuroprotective potential against glutamate toxicity.

Purpose of the Study:

• To design and synthesize novel dual TG2-HDAC binding agents.
• To evaluate the efficacy and safety of these agents in protecting neurons.

Main Methods:

• Synthesis of novel dual TG2-HDAC inhibitors.
• In vitro enzymatic assays to determine IC50 values for TG2, HDAC1, and HDAC6 inhibition.
• Cell-based assays using cortical neurons to assess neuroprotection against glutamate-induced toxicity and general toxicity.

Main Results:

• Compound 3 demonstrated potent inhibition of both TG2 (IC50 = 13.3 ± 1.5 μm) and HDACs (HDAC1 IC50 = 3.38 ± 0.14 μm, HDAC6 IC50 = 4.10 ± 0.13 μm).
• Compound 3 exhibited significant neuroprotection against glutamate toxicity in cortical neurons (EC50 = 3.7 ± 0.5 μm).
• No toxic effects were observed in cortical neurons at concentrations up to 50 μm.

Conclusions:

• Dual inhibition of TG2 and HDACs is a promising strategy for neuroprotection.
• Compound 3 is a potent and safe dual TG2-HDAC inhibitor with therapeutic potential for neurodegenerative conditions.