Derivatives of ERK-D domain inhibitor #76 exhibit greater potency in inhibiting the growth of JAK-dependent cells. (A) Selective inhibition of ERK2-mediated phosphorylation of RSK by the D-domain inhibitors #76, 30 g, and 30 h. SCID.adh cells were pretreated with the indicated inhibitors and then stimulated with PMA. Immunoblot analysis of protein extracts was performed with the following antibodies: anti-EGR1, anti–phospho-RSK, anti-RSK, anti–phospho-ERK, anti- ERK, and anti–β-actin, which served as a loading control. (B) Cell lines expressing JAK2V617F (SET-2, UKE-1, KU812, and BAF/3-JAK2) were treated with vehicle control, U0126, #76, 30 g, and 30 h at the indicated doses. All results are from ≥3 independent experiments. Cell viability and proliferation were measured after 1 day of culture and normalized to untreated cells at day 0. Data are expressed as the mean ± standard deviation. *P < .05; **P < .01; ***P < .001; ns, not significant.
Figure 7.

Derivatives of ERK-D domain inhibitor #76 exhibit greater potency in inhibiting the growth of JAK-dependent cells. (A) Selective inhibition of ERK2-mediated phosphorylation of RSK by the D-domain inhibitors #76, 30 g, and 30 h. SCID.adh cells were pretreated with the indicated inhibitors and then stimulated with PMA. Immunoblot analysis of protein extracts was performed with the following antibodies: anti-EGR1, anti–phospho-RSK, anti-RSK, anti–phospho-ERK, anti- ERK, and anti–β-actin, which served as a loading control. (B) Cell lines expressing JAK2V617F (SET-2, UKE-1, KU812, and BAF/3-JAK2) were treated with vehicle control, U0126, #76, 30 g, and 30 h at the indicated doses. All results are from ≥3 independent experiments. Cell viability and proliferation were measured after 1 day of culture and normalized to untreated cells at day 0. Data are expressed as the mean ± standard deviation. *P < .05; **P < .01; ***P < .001; ns, not significant.

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