Table 1. Discovery of LY2784544, a small molecule JAK2 inhibitor, more selective for JAK2 than for JAK3 in vitro and in vivo.
| JAK2 inhibitors |
Biochemical measurement of JAK inhibitiona, IC50±s.d., nℳ |
Cell-based assay of JAK inhibitionb, IC50±s.d., nℳ |
14-Day rat immunotoxicology |
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|---|---|---|---|---|---|---|---|
| JAK2 | JAK3 | EPO TF-1 JAK2 | IL-2 NK-92 JAK3/JAK1 | Plasma exposure mean AUC0-24 h, ng·h/ml |
Change in cytotoxic T-cells, CD3+CD8a+, % |
||
| Spleen | Peripheral blood | ||||||
| Compound 1 | 2 (n=1/6)c | 8±6 (n=6) | 35±13 (n=62) | 228±76 (n=61) | 4000–6000 | −42 (P<0.05)d | −39 (P<0.05) |
| Compound 2 (LY2784544) | 3±0.5 (n=4) | 48±15 (n=4) | 45±19 (n=8) | 942±255 (n=8) | 4000–4500 | No change | No change |
Abbreviations: AUC, area under the curve; EPO, erythropoietin; CD, cluster of differentiation; IC50, half maximal inhibitory concentration; JAK, janus kinase; IL, interleukin; n, number of experiments; s.d., standard deviation.
a
Used JAK LanthaScreen Kinase assay.
b
Used Cellomics detection format.
c
Results for 5/6 runs were less than 0 (compound concentration was too great), so results are reported only from a single run.
d
Statistical analysis was conducted using the MIXED procedure in SAS 9. Quantitative results for all immunotoxicology parameters were analyzed using a two-sample t-test at the 0.05 significance level.