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.

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.