Table 6. Inhibition of HAT-Catalyzed Histone Acetylation by Select Compounds Using an Orthogonal [3H]-Acetyl-CoA HAT Assaya.
| ID | Rtt109 HTS IC50 (μM)b | slot blot activity (125 μM)b | Rtt109 IC50 (μM) (−) DTT | p300 IC50 (μM) (−) DTT | Gcn5 IC50 (μM) (−) DTT | (+) DTT IC50 effectc |
|---|---|---|---|---|---|---|
| 1a | 8.8 | P | 15 (11–22) | 7.5 (3.0–19) | 11 (4.6–26) | increase |
| 1i | 6 | P | 4.6 (2.9–7.2) | 6.2 (1.8–21) | 20 (9.3–44) | increase |
| 1j | 6.6 | P | 3.4 (1.9–6.2) | 6.2 (3.8–10) | 3.7 (2.8–4.8) | increase |
| 1k | 4.6 | P | 6.1 (4.1–12) | 11 (3.1–38) | 11 (5.3–22) | increase |
| 2a | 2.8 | P | 3.9 (2.7–5.6) | 2.2 (1.7–2.9) | 4.6 (3.4–6.3) | increase |
| 2e | 2.3 | Y | 0.77 (0.67–1.1) | 1.1 (0.7–1.6) | 1.6 (0.7–3.9) | increase |
| 3a | 2.7 | Y | 0.81 (0.59–1.1) | 1.9 (1.4–2.5) | 7.5 (5.3–11) | increase |
| 3d | 2.7 | Y | 0.64 (0.55–1.3) | 1.8 (1.4–2.4) | 5.3 (3.9–7.2) | increase |
| 3f | 3.5 | Y | 1.7 (1.5–2.2) | 2.0 (1.6–2.5) | 8.1 (5.8–11) | increase |
| 4a | 15 | P | 3.9 (3.1–5.0) | 3.7 (1.1–13) | 27 (12–61)) | increase |
| 4b | 17 | P | 1.2 (0.7–2.1) | 2.8 (1.5–5.2) | 6.7 (2.7–16) | increase |
| 4e | 11 | Y | 8.6 (4.6–16) | 9.8 (7.1–14) | 27 (10–70) | increase |
| 6a | NA | Y | 0.52 (0.45–1.7) | 1.0 (0.9–1.2) | 0.65 (0.3–1.2) | increase |
| 6b | 1.5 | Y | 0.67 (0.63–1.4) | 0.51 (0.40–1.4) | 2.5 (1.7–3.8) | increase |
| 6c | NA | Y | 0.15 (0.12–0.51) | 0.66 (0.57–1.3) | 1.3 (0.9–1.9) | increase |
| 6d | 3.9 | Y | 4.3 (3.1–6.0) | 3.1 (2.6–3.7) | 4.3 (2.3–7.7) | increase |
| 6e | 2.5 | Y | 1.6 (1.2–2.1) | 1.8 (1.3–2.5) | 1.2 (0.7–1.9) | increase |
| 6f | 0.91 | Y | 1.7 (1.4–1.9) | 1.1 (0.7–1.6) | 5.2 (4.0–6.7) | increase |
| 6y | NA | Y | 0.13 (0.12–0.64) | 0.33 (0.30–2.3) | 1.2 (0.9–1.7) | increase |
| CPM | Y | 0.26 (0.20–0.27) | 0.26 (0.23–0.35) | 1.1 (0.9–1.2) | increase | |
| garcinol | 13d | Y | 3.5 (3.3–3.8) | 1.7 (0.9–3.1) | 2.6 (1.4–4.9) | none |
| fluconazole | inactive | inactive | inactive | inactive | inactive | none |
a
In parentheses are the 95% confidence intervals for the IC50 values.
c
Compounds tested identically in the presence of 1 mM DTT; results similar versus Rtt109-Vps75, p300, and Gcn5; typically <20% inhibition was observed at 125 μM final compound concentrations.
d
Previously published value.42