MEK5 is a dual specificity protein kinase that belongs to the mitogen-activated protein kinase family. This kinase specifically interacts with and activates MAPK7/ERK5. The signal cascade mediated by this kinase is involved in growth factor stimulated cell proliferation and muscle cell differentiation. BIX-02189 is a selective inhibitor of MEK5 with IC50 value of 1.5nM. BIX-02189 also inhibits ERK5, TGFβR1, ABL1, CSF1R, JAK3, KIT, LCK, MAPK14, RPS6KA3,RPS6KA6 and SRC with IC50 values of 59nM, 580nM, 2400nM, 46nM, 1000nM, 440nM, 1100nM, 250nM, 3700nM, 2100nM, 990nM and 7600nM, respectively. In vitro, BIX-02189 inhibited Hela and HEK293cells with IC50 values of 0.53nM and 0.26nM, respectively[3]. Treatment A549 lung cancer cells with 2.5-10μM BIX-02189 completely hindered the EGF-induced phosphorylation of ERK5 in a concentration-dependent manner without affecting the phosphorylation of ERK1/2. BIX02189 significantly abolished TGF-β1-mediated E-cadherin repression and N-cadherin induction. In addition, BIX02189 inhibited TGF-β1-induced cell motility and activation of MMP-2 in A549 lung cancer cells. In vivo, Intraperitoneal administration of BIX-02189 at 20mg/kg once daily for 3 weeks inhibited TGF-β receptor type I (TβRI) derived lung metastasis in TβRI-derived A549 xenograft mouse model[4].
作用机制
BIX-02189 inhibits catalytic function of MEK5 and blocks phosphorylation of ERK. [5].
(E/Z)-BIX02189 细胞实验
Cell Line
Concentration
Treated Time
Description
References
neonatal rat cardiomyocytes (NRCMs)
10μM
2 h
Inhibited ERK5 phosphorylation, attenuated MEF2 transcriptional activity, and blunted the hypertrophic response in cardiomyocytes
Circ Res. 2010 Mar 19;106(5):961-70.
Human umbilical vein endothelial cells (HUVECs)
10 μM
16–24 h
To investigate the role of ERK5 in laminar flow-induced Nrf2 nuclear translocation. Results showed that BIX02189 inhibited laminar flow-induced Nrf2 nuclear translocation.
J Biol Chem. 2012 Nov 23;287(48):40722-31.
PC12 cells
30 μM
30 min
To investigate the role of ERK5 signaling in PC12 cells, results showed that BIX02189 selectively inhibited ERK5 phosphorylation without affecting ERK1/2 phosphorylation status.
J Biol Chem. 2009 Aug 28;284(35):23564-73.
INS-1 cells
2 μM
9 h
To evaluate the role of ERK5 in STZ-induced apoptosis in INS-1 cells. Results showed that BIX02189 pretreatment significantly increased the cleavage levels of PARP-1 and caspase-3 induced by STZ, indicating that ERK5 inhibition exacerbated STZ-induced apoptosis.
Mol Cells. 2017 Jul 31;40(7):457-465
Rat superior cervical ganglion neurons
10 μM
48 h
To evaluate the selective inhibition of MEK5-ERK5 signaling by BIX02189, results showed that BIX02189 alone or in combination with PD184352 had no significant effect on WldS-mediated axon protection.
PLoS One. 2013 Oct 4;8(10):e76505
C2C12 myoblasts
10 μM
20 min
To investigate the role of MEK5/ERK5 pathway in PMA-induced mTORC1 signaling activation. BIX-02189 partially prevented PMA-induced phosphorylation of S6K1 (41% decrease in Thr389 phosphorylation and 29% decrease in Ser421/Thr424 phosphorylation) and completely blocked ERK5 phosphorylation.
FEBS Open Bio. 2017 Jan 30;7(3):424-433
(E/Z)-BIX02189 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Pregnant mouse model
Intraperitoneal injection
10 mg/kg
Once daily from gestational day 1 to day 15
To suppress ERK5 activation and study its effect on beta-cell proliferation in pregnant mice, results showed that BIX02189 significantly reduced beta-cell proliferation, leading to increased blood glucose levels and impaired glucose response
Cell Prolif. 2018 Jun;51(3):e12410
C57BL/6 mice
Nrf2 nuclear translocation model in aortic endothelial cells
Intraperitoneal injection
10 mg/kg
Single dose
To investigate the effect of ERK5 on Nrf2 nuclear translocation in vivo. Results showed that BIX02189 inhibited Nrf2 nuclear translocation in aortic endothelial cells of mice.
J Biol Chem. 2012 Nov 23;287(48):40722-31.
C57BL/6J mice
STZ-induced type 1 diabetes model
Intraperitoneal injection
10 mg/kg
Every 2 days for 6 days
To evaluate the effect of ERK5 inhibition on STZ-induced hyperglycemia and pancreatic β-cell apoptosis. Results showed that co-treatment with BIX02189 and STZ significantly exacerbated hyperglycemia and pancreatic β-cell apoptosis, indicating that ERK5 inhibition aggravated diabetic symptoms.
搜索
