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HomeProduct name listAS703026

AS703026

AS703026 Structural

What is AS703026?

The Uses of AS703026

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.

What are the applications of Application

AS703026 is a potent inhibitor of MEK1 and MEK2

Definition

ChEBI: N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide is a pyridinecarboxamide.

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].

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.

Properties of AS703026

Boiling point: 623.2±55.0 °C(Predicted)
Density  1.769
storage temp.  Store at -20°C
solubility  ≥21.55 mg/mL in DMSO; insoluble in H2O; ≥10.36 mg/mL in EtOH with ultrasonic
form  solid
pka 12.82±0.46(Predicted)
color  Light yellow to khaki

Safety information for AS703026

Signal word Warning
Pictogram(s)
ghs
Exclamation Mark
Irritant
GHS07
GHS Hazard Statements H315:Skin corrosion/irritation
H319:Serious eye damage/eye irritation
H335:Specific target organ toxicity, single exposure;Respiratory tract irritation
Precautionary Statement Codes P301+P312:IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P302+P352:IF ON SKIN: wash with plenty of soap and water.
P305+P351+P338:IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

Computed Descriptors for AS703026

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