An ERK5 inhibitor
XMD8-85 is an ERK5 inhibitor (IC50 = 87 nM in an enzyme assay).1 It is selective for ERK5 over tyrosine non-receptor kinase 2 (TNK2; IC50 = 959 nM), but does inhibit the leucine-rich repeat kinase 2 (LRRK2) mutant LRRK2G2019S (IC50 = 26 nM), which has been found in patients with Parkinson’s disease.2,1 XMD8-85 inhibits EGF-induced ERK5 autophosphorylation in HeLa cells (EC50 = 0.19 μM).1
1.Deng, X., Elkins, J.M., Zhang, J., et al.Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-onesEur. J. Med. Chem.70758-767(2013) 2.Groendyke, B.J., Powell, C.E., Feru, F., et al.Benzopyrimidodiazepinone inhibitors of TNK2Bioorg. Med. Chem. Lett.30(4)126948(2020)
Kinase experiment: | Kinase activity is determined in an assay volume of 40 μL in kinase buffer (50 mM Tris-HCl, pH 7.5, 0.1 mM EGTA, 1 mM 2-mercaptoethanol) containing 200 ng of pure active ERK5 and the indicated amount of inhibitor. Reaction started by adding 10 mM magnesium acetate, and 50 μM [γ-32P]-ATP (500 cpm/pmol) and 250 μM PIMtide (ARKKRRHPSGPPTA) as substrates. Assays are carried out for 20 min at 30°C, terminated by applying the reaction mixture onto p81 paper and the incorporated radioactivity measured[1]. |
参考文献: [1]. Deng X, et al. Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones. Eur J Med Chem. 2013;70:758-767. | |
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