NUAK family SNF1-like kinase-1 (NUAK1) and NUAK2 are the members of the AMPK family that play important roles in regulating essential cellular events, such as cell invasion, proliferation, embryonic development and axon branching. WZ4003 is an inhibitor of both NUAK isoforms with IC50 values of 20 nM and 100 nM for NUAK1 and NUAK2, respectively. In HEK-293 cells, EDTA-induced phosphorylation of MYPT1 at Ser445 was suppressed by WZ4003 (0.3 - 10 mM) in a dose-dependent manner. In HEK-293 cells expressing drug-resistant NUAK1[A195T], WZ4003 at 30 μM failed to block the phosphorylation of MYPT1. However, WZ4003 at 3 - 10 μM effectively suppressed MYPT1 Ser445 phosphorylation. Treatment with 10 μM WZ4003 remarkably reduced cell migration in wild-type mouse embryonic fibroblasts (MEFs). In both U2OS cells and MEFs, WZ4003 at 10 μM suppressed cell proliferation and MYPT1 phosphorylation to the same level as shown in NUAK1 knockout cells. The invasion potential of U2OS cells was also inhibited by 10 μM WZ4003[3]. In the Ba/F3 cell line, the IC50 values of WZ4003 against L858R/T790M mutant and T790M mutant were 1.90 mM and 1.29 mM, respectively[4].
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