J. P. Malerich et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7454–7457
7457
inhibitors, and then examined the levels of IFN
c
, a downstream
product of IL-12 signaling. We found that compounds 11, 19, and
20 inhibited IFN production similar to JNJ-7706621 (1) whereas
compounds 13 and 15 partially inhibited IFN (Fig. 3). Compounds
16 and 17 were included as negative controls since they showed no
activity in the kinase assay. They showed minimal IFN inhibition.
c
c
c
In conclusion, we have identified four compounds, 11, 15, 19,
and 20, with activity and selectivity similar to the most selective
compound described in the literature JNJ-7706621 (1). Compounds
11, 15, and 20 maintain activity in a cellular context. Our future ef-
forts will be directed toward developing compounds with higher
selectivity for TYK2 over JAK1-3. Work will be guided by the new
crystal structures, and we will seek new opportunities to achieve
selectivity in this family of kinases.
Supplementary data
Supplementary data (synthetic procedures, NMR spectra of
compounds 11–26, and methods for enzymatic inhibition assays)
associated with this article can be found, in the online version, at
References and notes
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Figure 3. Inhibitory effect of compounds on IFN
blasts, from two different donors were derived from PBMCs cultured in PHA (0.1
ml) and IL-2 (10 U/ml) for 7 days. PHA blasts were pre-incubated with inhibitors
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Next, we sought to determine whether these triazoles would
also be capable of inhibiting TYK2 in a biologically relevant setting.
We stimulated human PHA blasts with IL-12, a cytokine which re-
quires TYK2 and JAK2 for signaling, in the absence or presence of