Table 2. HDAC Selectivity, Potency, and Efficacy of 6 Compared To SAHAa.
| assay | 6 | SAHA |
|---|---|---|
| IC50 (nM) | ||
| HDAC 1 | 0.3 | 4.0 |
| HDAC 2 | 2.0 | 11 |
| HDAC 3 | 0.6 | 3.0 |
| HDAC 4 | 1970 | >30000 |
| HDAC 5 | 352 | 8750 |
| HDAC 6 | 4.1 | 2.0 |
| HDAC 7 | >20000 | >30000 |
| HDAC 8 | >15000 | 1020 |
| HDAC 9 | >15000 | >30000 |
| EC50 (nM) | ||
| H3K9ac | 100 | 3400 |
| H4K12ac | 100 | 1900 |
a
In vitro IC50 (nM) values using recombinant human enzymes for HDAC subtypes 1–9 and specific substrates demonstrate that 6 is a selective inhibitor of HDAC 1–3 (0.3–2.0 nM) with decreased potency to inhibit HDAC 6 (4.1 nM) or other subtypes (>352 nM). Comparatively, the hydroxamate HDAC inhibitor SAHA exhibited lower affinity for HDAC targets 1–3 (3.0–11 nM). Dose–response plots in cultured primary mouse neuronal cells measuring relative H3K9ac and H4K12ac levels revealed potent induction of histone acetylation (EC50) by 6 (100 nM) compared to SAHA (1900–3400 nM).