Table 2 In vitro activity and in silico data of the main HDAC6 specific inhibitors
From: HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?
Tubacin | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Â | Inhibition of HDAC isoforms | ||||||||||
| Â | Class I | Class II | Class IV | ||||||||
| Â | HDAC1 | HDAC2 | HDAC3 | HDAC8 | HDAC4 | HDAC5 | HDAC7 | HDAC9 | HDAC6 | HDAC10 | HDAC11 |
IC 50 (nM) | 1400 [40] | 6270 [40] | 1270 [40] | 1270 [40] | 17300 [40] | 3350 [40] | 9700 [40] | 4310 [40] | 4 [40] | - | 3790 [40] |
995 [62] | - | - | 6100 [62] | - | - | - | - | 28 [62] | - | - | |
In silico data | Homology modeling, molecular docking and molecular dynamics simulations highlight differences between HDAC1, HDAC6 and HDAC8 [37] | ||||||||||
In vitro | Model | Outcomes | Observed in | ||||||||
AD | Decrease of tau phosphorylation with no disruption of HDAC6-tau interaction [32] | Human embryonic kidney cells (HEK) and HEK cells stably expressing tau (HEK-tau) [32] | |||||||||
PD | Block of the centrosomal recruitment of parkin [63] | HEK-293T and SH-SY5Y cells [63] | |||||||||
Block of the formation of aggresome-like bodies and interference with autophagy [64] | Rat pheochromocytoma cell line (PC12) and SH-SY5Ys [64] | ||||||||||
HD | Neuroprotection [65] | Mouse striatal cells derived from WT htt mice and from HdhQ109 knock-in mice, HEK-293 cells, Cos7 cells, primary cortical neurons [65] | |||||||||
ND and Co | Disruption of autophagic degradation of aggregated huntingtin [66] | Neuro2a [66] | |||||||||
Neuroprotection against oxidative stress [67] | LNCaP, Du145, PC3 HFS and LAPC4 cells [67] | ||||||||||
| Â | Improvement of mitochondrial movement [68] | Rat hippocampal neurons [68] | |||||||||
Mercaptoacetamide derivative | |||||||||||
| Â | Inhibition of HDAC isoforms | ||||||||||
| Â | Class I | Class II | Class IV | ||||||||
| Â | HDAC1 | HDAC2 | HDAC3 | HDAC8 | HDAC4 | HDAC5 | HDAC7 | HDAC9 | HDAC6 | HDAC10 | HDAC11 |
IC 50 (nM) | 3220 [69] | 7380 [69] | - | - | - | - | - | - | 95 [69] | 10700 [69] | - |
In vitro | Model | Outcomes | Observed in | ||||||||
ND and Co | Neuroprotection against oxidative stress [69] | Rat cortical neurons [69] | |||||||||
Tubastatin A | |||||||||||
| Â | Inhibition of HDAC isoforms | ||||||||||
| Â | Class I | Class II | Class IV | ||||||||
| Â | HDAC1 | HDAC2 | HDAC3 | HDAC8 | HDAC4 | HDAC5 | HDAC7 | HDAC9 | HDAC6 | HDAC10 | HDAC11 |
IC 50 (nM) | 16400 [40] | >30000 [40] | >30000 [40] | 8540 [40] | >30000 [40] | >30000 [40] | >30000 [40] | >30000 [40] | 15 [40] | >30000 [40] | >30000 [40] |
In silico data | Homology modeling and molecular docking highlight differences between HDAC1 and HDAC6 [40] | ||||||||||
In vitro | Model | Outcomes | Observed in | ||||||||
ND and Co | Neuroprotection against oxidative stress [40] | Rat primary cortical neurons [40] | |||||||||
M344 | |||||||||||
| Â | Inhibition of HDAC isoforms | ||||||||||
| Â | Class I | Class II | Class IV | ||||||||
| Â | HDAC1 | HDAC2 | HDAC3 | HDAC8 | HDAC4 | HDAC5 | HDAC7 | HDAC9 | HDAC6 | HDAC10 | HDAC11 |
IC 50 (nM) | 249 [70] | - | - | - | - | - | - | - | 88[70] | - | - |
In vitro | Model | Outcomes | Observed in | ||||||||
AD | Effect on Aβ pathology [71] | Human neuroblastoma cells; rat hippocampal neurons, primary astrocytes, cerebral cortices and midbrain [71] | |||||||||
WT-161 | |||||||||||
In vitro | Model | Outcomes | Observed in | ||||||||
Myeloma cells | Increased acetylated α-tubulin (K40) over total acetylated lysine at 2 μM | Human MM1.S cells | |||||||||
In vivo | Model | Outcomes | Observed in | ||||||||
Co | Increased acetylated α-tubulin (K40) [52] | Area CA1 of hippocampus from mice treated with WT-161 at 25 mg/kg i.p. during 10 days [52] | |||||||||
| Â | Â | Did not improve cognition [52] | Memory test in mice treated with WT-161 at 25 mg/kg i.p. during 10 days [52] | ||||||||