Inhibition of human 2OG oxygenases by selected derivatives of N-hydroxythiazole 4 with modifications to the methylene sulfone linker.
| Entry | Cmpd |
|
IC50 [μM]a | ||||
|---|---|---|---|---|---|---|---|
| R | FIHb | PHD2c | AspHd | KDM4Ae | JMJD5f | ||
| i | 4 |
|
0.28 ± 0.00 | 0.50 ± 0.05 | 9.6 ± 1.3 | >100 | 0.48 ± 0.01 |
| ii | 14 | Me | 52.4 ± 30.4 | >100 | >100 | >100 | 3.2 ± 0.7 |
| iii | 15 |
|
0.30 ± 0.05 | 2.7 ± 0.2 | 33.0 ± 12.1 | >100 | 3.3 ± 1.5 |
| iv | 16 |
|
1.2 ± 0.2 | 1.2 ± 0.2 | 2.4 ± 1.1 | >100 | 1.7 ± 0.3 |
| v | 17 |
|
4.6 ± 0.7 | 3.6 ± 0.4 | 28.3 ± 6.5 | >100 | 4.6 ± 1.7 |
| vi | 18 |
|
6.0 ± 1.2 | 2.3 ± 0.1 | 3.7 ± 1.5 | >100 | 8.4 ± 2.7 |
| vii | 19 |
|
3.7 ± 1.5 | 15.5 ± 4.6 | 3.1 ± 0.4 | 17.4 ± 0.2 | 12.0 ± 0.6 |
| viii | 20 |
|
1.0 ± 0.1 | 6.5 ± 1.8 | 23.3 ± 10.1 | >100 | 13.4 ± 6.5 |
| ix | 21 |
|
0.36 ± 0.21 | 0.57 ± 0.18 | 0.76 ± 0.10 | >100 | 2.8 ± 0.9 |
| x | 22 |
|
0.75 ± 0.23 | 2.6 ± 0.2 | 20.2 ± 6.6 | >100 | 1.2 ± 0.2 |
| xi | 23 |
|
3.2 ± 1.1 | 10.3 ± 2.9 | 11.1 ± 0.4 | 71.6 ± 11.8 | 4.7 ± 1.1 |
a
Mean average ± SD of two independent experiments (each composed of technical duplicates).
b
Using 0.15 μM FIH, 10.0 μM 2OG and 5.0 μM HIF-1α C-TAD788–822.61
c
Using 0.15 μM PHD2181–426 and 5.0 μM HIF-1α CODD556–574.61
d
Using 0.05 μM His6-AspH315–758, 3.0 μM 2OG and 1.0 μM hFX-CP101–119.
e
Using 0.15 μM KDM4A, 10.0 μM 2OG and 10.0 μM H31–15K9me31–15.69
f
Using 0.15 μM JMJD5, 2.0 μM 2OG and 2.0 μM RSP6128–148.70 Inhibition assays were performed using SPE-MS as described in the ESI.