Pimasertib (AS-703026)

Oral gavage twice daily

U266 and INA-6 cells

AS703026 is currently under Phase II clinical trial for acute myeloid leukemia.

AS703026 is a highly selective and potent non-competitive inhibitor of MEK1/2 with IC50 of 5-11 nM.

AS703026 is a novel, highly selective and potent allosteric inhibitor of MEK1/2.

5-11 nM [1], 5-11 nM [1], 5-11 nM [1], 5-11 nM [1], 5-11 nM [1], 5-11 nM [1]

AS703026 (15 and 30 mg/kg) significantly inhibits tumor growth in a human plasmacytoma xenograft model of H929 MM cells. This can be correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels. [1] AS703026 (10 mg/kg) inhibits tumor growth, and markedly decreases p-ERK level in a xenograft mouse model of human K-Ras mutated (D-MUT) colorectal tumor. [2]

[3], MEK1 enzyme assays, AS703026 is dissolved in 2.5% DMSO. Activated diphosphorylated MEK (pp-MEK) assays contained 40 uM 33P-gammaATP (AppKm 8.5 uM), 0.5 nM human-activated MEK1 or MEK2, 1 uM kinase-dead ERK2 (AppKm 0.73 uM). All assays are done in buffer containing 20 mM HEPES (pH 7.2), 5 mM 2-mercaptoethanol, 0.15 mg/mL BSA, and 10 mM MgCl2. The final concentration of 33P- ATP is 0.02 uCi/uL for all the assays. pp-MEK kinase reactions are stopped after 40 min by transferring 30 uL of reaction mixture to Durapore 0.45-um filters plates containing 12.5% TCA. Filters are dried and read with liquid scintilant on a TopCount. Concentration response data are analyzed for IC50. 0.2 nM recombinant human MEK1 or MEK2 is preincubated with vehicle or with AS703026 for 40 minutes in reaction buffer to determine IC50 of initially unphosphorylated MEK (u-MEK). Phosphorylation/activation is initiated by the addition of a final concentration of 20 nM final B-RafV600E and 30 uM final ATP for 10 min. B-Raf activity is then quenched by addition of the B-Raf inhibitor SB590885 (final concentration 100 nM), and MEK kinase activity is assayed by the addition of 1 uM KD-ERK2 and 0.02 uCi/uL 33P-ATP in reaction buffer. The kinase reactions are stopped after 90 min by transferring 30uL of reaction mixture to a Durapore filter plate, and read as above.

431, 2

, , Dr. Zhang of Tianjin Medical University, AS703026purchased from Selleck, After starved in serum-free medium for 24h, T47D cells incubated with the indicated concentrations of AS703026 for 3h, followed by 20-minute stimolation of 100ng/ml EGF.

2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO