AS703026

AS703026 (Pimasertib; MSC1936369B) is a potent, selective, allosteric, orally bioavailable MEK1/2 inhibitor, inhibits the growth of MM cell lines with IC50 of 0.005-2 uM; has IC50 of 10 nM against INA-6 cells, approximately 10-fold more potent than AZD6244 at inhibiting cytokine-induced osteoclast differentiation in vitro; effectively inhibits the growth of D-MUT cells in vitro and in vivo by specific inhibition of the key MEK downstream target kinase ERK; also enhances gemcitabine efficacy in pancreatic cancer models by reducing ribonucleotide reductase subunit-1 (RRM1) .Skin Cancer Phase 2 Clinical (In Vitro) :Pimasertib (5, 0.5, and 0.1 μM) specifically blocks ERK1/2 activation in MM cells, cultured alone or with BMSCs. Pimasertib inhibits the growth of MM cell lines in a dose-dependent manner, with IC50s ranging from 0.005 to 2 μM. The IC50s of Pimasertib against INA-6, U266, H929 cells are 10 nM, 5 nM, 200 nM respectively. Pimasertib induces apoptosis and modulates the cell cycle profile. Pimasertib targets MM cells in the BM microenvironment. Pimasertib (10 μmol/L) inhibits ERK pathway, proliferation, and transformation in cetuximab-resistant D-MUT cells. Pimasertib in combination with PLX4032 significantly induces apoptosis of RPMI-7951 cells, whereas each drug used alone does not. Pimasertib synergizes with small interfering RNA-mediated downregulation of BRAF to produce results similar to those of combined treatment with PLX4032 and Pimasertib. (In Vivo) :Pimasertib (15, 30 mg/kg) significantly inhibits the growth of tumor in the human H929 MM xenograft model in CB17 SCID mice. Pimasertib (10 mg/kg, p.o.) inhibits tumor growth of cetuximab-resistant tumor attributed by K-ras mutation.