Description
As a novel, selective, orally bioavailable inhibitor, AS703026 can inhibit MEK1/2 with IC50 of with IC50 of 5-11 nM.
Storage
2 years at -20 centigrade
Molecular Formula
C15H15FIN3O3
Chemical Name
(S)-N-(2,3-dihydroxypropyl)-3-(2-fluoro-4-iodophenylamino)isonicotinamide
Solubility
DSMO 86 mg/mL Water
In vitro
As a novel, selective, orally bioavailable inhibitor, AS703026 can inhibit MEK1/2 with IC50 of with IC50 of 5-11 nM. For cell lines, (1)AS703026 effectively inhibited the growth of D-MUT cells in vitro and in vivo by specific inhibition of the key MEK downstream target kinase ERK. Inhibition of MEK by AS703026 suppressed cetuximab-resistant colorectal cancer cells attributed to K-ras mutation both in vitro and in vivo. (2)AS703026 also inhibit growth and survival of MM (human multiple myeloma) cells and cytokine-induced osteoclast differentiation more potently (9- to 10-fold) than AZD6244. Inhibition of proliferation induced by AS703026 was mediated by G0-G1 cell cycle arrest and was accompanied by reduction of MAF oncogene expression. AS703026 further induced apoptosis via caspase 3 and Poly ADP ribose polymerase (PARP) cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs).
In vivo
AS703026 sensitized MM cells to a broad spectrum of conventional (dexamethasone, melphalan), novel or emerging (lenalidomide, perifosine, bortezomib, rapamycin) anti-MM therapies. Significant tumour growth reduction in AS703026- vs. vehicle-treated mice bearing H929 MM xenograft tumours correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels in vivo. AS703026, at the concentration less than 200 nM, was cytotoxic against the majority of tumour cells tested from patients with relapsed and refractory MM, regardless of mutational status of RAS and BRAF genes.
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