BIX02188 is a selective and potent MEK5 inhibitor that inhibits MEK5-induced apoptosis in cells expressing the oncogenic mutant FLT3-ITD.

RPS6KA6/RSK4:3.2 μM, ERK5:810 nM, RPS6KA3/RSK2:4.1 μM, SRC:8.9 μM, LCK:390 nM, CSF1R (FMS):280 nM, c-Kit:550 nM, JAK3:7.8 μM, MAPK14 (p38 alpha):3.9 μM, MEK5:4.3 nM, TGFβRI:1.8 μM, Abl-1:2.1 μM

BIX02188 is a potent MEK5 enzyme inhibitor that selectively blocks ERK5 phosphorylation in activated HeLa cells, without impacting the phosphorylation of ERK1/2, JNK, and p38 MAP kinases. Its specificity was further demonstrated in studies with cultured endothelial cells (EC) and bovine lung microvascular endothelial cells (BLMECs), where BIX02188 dose-dependently inhibited BMK1 phosphorylation induced by H2O2 activation, displaying an IC50 of 0.8±1.0 μM. Notably, BIX02188 did not significantly inhibit ERK1/2 and JNK at concentrations ranging from 0.1-10 μM, underscoring its selective action on MEK5-induced BMK1 phosphorylation. Additionally, BIX02188 exhibited strong inhibitory effects on MEK5 and ERK5 activities, with IC50 values of 4.3 nM and 810 nM, respectively, and did not inhibit closely related kinases such as MEK1, MEK2, ERK2, and JNK2. In podocyte studies, pre-incubation with BIX02188 mitigated the pro-fibrotic stimulus-induced proliferation by TGFβ1, highlighting its potential utility in reducing podocyte cell number through the inhibition of Erk5 activation. This comprehensive evaluation demonstrates BIX02188's efficacy and specificity in inhibiting MEK5/ERK5 pathway components, offering valuable insights for therapeutic strategies targeting specific kinase activities.