Table 2.
JAK- and domain-selectivity of selected hits or analogs and effects on MPN cells. Binding of selected hits or analogs to JAK2 JH2 V617F mutant, JH2 and JH1 domains of JAK family members, and effect on cell viability of MPN cell lines HEL and SET-2. Data is presented as IC50 [µM] obtained by fitting dose vs. normalized response across multiple replica data sets (n = 3–9).
| Compound | Binding IC50 [µM] |
Cell Viability IC50 [µM] | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| JAK2 | JAK1 | JAK3 | TYK2 | HEL | SET-2 | |||||||
| JH2 V617F | JH2 | JH1 | JH2 | JH1 | JH2 | JH1 | JH2 | JH1 | ||||
| Diaminotriazole | 1 | 0.32 | 0.31 | 0.04 | 0.004 | 0.08 | 7.2 | 0.15 | 0.14 | 0.04 | 5.6 | 5.8 |
| 18 | 69 | 67 | ND | 41 | ND | 15 | ND | ND | ND | ND | ND | |
| Diaminotriazine | 4 | 26 | 68 | ND | 4.5 | ND | ND | ND | 27 | ND | ND | ND |
| 24 | 24 | 70 | ND | ND | ND | ND | ND | ND | ND | ND | ND | |
| Aminopurine | 7 | 1.9 | 1.3 | 0.68 | 0.15 | 0.35 | 4.7 | 0.30 | 0.06 | 0.12 | 9.3 | 4.0 |
| Phenylpyrazolo-pyrimidone | 34 | 39 | 14 | ND | ND | ND | 28 | 70 | 9.7 | 50 | ND | ND |
| 36 | 47 | 25 | ND | ND | ND | ND | ND | 32 | ND | ND | ND | |
| Pyrazolyl-formamide | 2 | 7.7 | 5.8 | 0.05 | 0.11 | 0.06 | 11 | 0.07 | 0.04 | 0.02 | 1.3 | 0.54 |
ND, inhibition not detected or IC50 is above upper detection limit (100 µM in binding assay, 40 µM in cell viability assay). Compound abbreviations: 1, JNJ-7706621; 18, JS-014C; 4, CB_7644166; 24, Z53013220; 7, Reversine; 34, HTS02998; 36, HTS02993; 2, AT-9283.