AS-703026

AS703026

Solid.

1236699-92-5

32160000

liquid

InChI=1S/C15H15FIN3O3/c16-12-5-9(17)1-2-13(12)20-14-7-18-4-3-11(14)15(23)19-6-10(22)8-21/h1-5,7,10,20-22H,6,8H2,(H,19,23)/t10-/m0/s1

VIUAUNHCRHHYNE-JTQLQIEISA-N

Chemical. CAS: 1236699-92-5. Formula: C15H15FIN3O3. MW: 431.2. AS703026 is a novel, selective, non-competitive, orally bioavailable MEK1/2 inhibitor with experimental IC(50) values of 5-11nM. In use on multiple myeloma cells (MM), AS703026 inhibited growth and survival of MM cells and cytokine-induced osteoclast differentiation more potently (~10X) 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). Importantly, 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. Moreover, AS703026 (<200nM) was cytotoxic against the majority of tumour cells tested from patients with relapsed and refractory MM (84%), regardless of mutational status of RAS and BRAF genes. Importantly, BMSC-induced viability of MM patient cells was similarly blocked within the same dose range.

C15H15FIN3O3

431.2

Plastic Vial

AS703026 is a novel, selective, non-competitive, orally bioavailable MEK1/2 inhibitor with experimental IC(50) values of 5-11nM. In use on multiple myeloma cells (MM), AS703026 inhibited growth and survival of MM cells and cytokine-induced osteoclast differentiation more potently (~10X) 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). Importantly, 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. Moreover, AS703026 (< 200nM) was cytotoxic against the majority of tumour cells tested from patients with relapsed and refractory MM (84%), regardless of mutational status of RAS and BRAF genes. Importantly, BMSC-induced viability of MM patient cells was similarly blocked within the same dose range.

>95%

Soluble in DMSO. Slightly soluble (<1mg/ml) in ethanol.

Non-hazardous

Protein Kinase Modulators

12352200

Stable for at least 1 year after receipt when stored at +4°C.