1236699-92-5 Usage
Uses
AS703026 is a novel, selective, orally bioavailable MEK1/2 inhibitor, in human multiple myeloma (MM). AS703026 induces pleiotropic anti-myeloma activity in vitro and in vivo. MEK inhibitors are useful in the treatment of hyperproliferative diseases, such as cancer, restenosis and inflammation.
Biological Activity
the mek/erk pathway transmits mitogenic signals to the nucleus and thus regulates the expression of genes that are critical for survival, proliferation, and differentiation. this pathway is often upregulated in cancer as result of oncogenic mutations. mek is a crucial kinase in this pathway and has been targeted for the therapeutic agents development that block the mek/erk signaling cascade. as 703026 is a novel small molecule mek inhibitor.
in vitro
as 703026 binds to the distinctive mek allosteric site and therefore exhibits exquisite kinase selectivity. the as 703026 binding to mek is independent of atp, and results in enzyme inhibition by prevention of activation. this inhibitor shows strong antiproliferative effect on tumor cell lines bearing oncogenic mutations or amplifications along the mek/erk pathway [1].
Enzyme inhibitor
This novel and orally bioavailable MEK1/2 inhibitor (FW = 431.20 g/mol; CAS 1236699-92-5), also known as (S)-N-(2,3-dihydroxypropyl)-3-((2- fluoro-4-iodophenyl)amino)-isonicotinamide, selectively targets MEK1/2 (noncompetitive, with IC50 values of 5-11 nM). AS703026 reduces the growth and survival of multiple myeloma (MM) cells. It also inhibits cytokine-induced osteoclast differentiation about 10x more potently than AZD6244. Inhibition of proliferation by AS703026 leads to G0-G1 cell cycle arrest, attended by reduction in MAF oncogene expression. AS703026 also induces apoptosis (via Caspase-3) as well as poly(ADP- ribose) polymerase (PARP) cleavage in MM cells, whether in the absence or presence of bone marrow stromal cells (BMSCs). Importantly, AS703026 also sensitizes MM cells to other anti-MM therapies employing dexamethasone, melphalan, lenalidomide, perifosine, bortezomib, or rapamycin. Growth reduction in mice bearing H929 MM xenograft tumors correlates with down-regulated pERK1/2, induced PARP cleavage, and decreased microvasculature. BMSC-induced viability of MM patient cells was similarly blocked within the same dose range.
in vivo
in relevant mouse xenograft models, as 703026 inhibits tumor growth after oral administration. the effect on tumor growth is dose-dependant and correlates with target modulation in both tumors and blood [1].
IC 50
ranging from 0.005 to 2 μm for the growth of mm cell lines
references
[1] goutopoulos a, askew bc, bankston d, clark a, dhanabal m, dong r, fischer d, healey b, jiang x, josephson k, lin j, ma j, noonan t, qiu d, rocha c, romanelli a, shutes a, spooner e, tian h, h y. as703026: a novel allosteric mek inhibitor. aacr annual meeting. 2009 abstract#4776.[2] macarulla t, cervantes a, tabernero j et al. phase i study of folfiri plus pimasertib as second-line treatment for kras-mutated metastatic colorectal cancer. br j cancer. 2015 jun 9;112(12):1874-81.
Check Digit Verification of cas no
The CAS Registry Mumber 1236699-92-5 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,2,3,6,6,9 and 9 respectively; the second part has 2 digits, 9 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 1236699-92:
(9*1)+(8*2)+(7*3)+(6*6)+(5*6)+(4*9)+(3*9)+(2*9)+(1*2)=195
195 % 10 = 5
So 1236699-92-5 is a valid CAS Registry Number.
1236699-92-5Relevant articles and documents
SOLID STATE FORMS OF N-((S)-2,3-DIHYDROXY-PROPYL)-3-(2-FLUORO-4-IODO-PHENYLAMINO)-ISONICOTINAMIDE
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Page/Page column 30, (2014/01/07)
The invention relates to solid state forms of N-((S)-2,3-Dihydroxy- propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide or its pharmaceutically acceptable salts, processes for their preparation, e.g. formula (I) and medical uses thereof.
