PD-325901, Free Base (PD 0325901, MEK1/2 Inhibitor III)

A selective and ATP non-competitive MEK inhibitor that suppresses the phosphorylation of ERK in murine colon 26 tumors (IC50 = 0.33nM). In combination with the GSK-3 inhibitor CHIR99021, prevents cell differentiation and sustains self-renewal of embryonic stem (ES) cells. PD 325901 is an inhibitor of mitogen activated protein kinase kinase (MEK or MAPKK). The potency, solubility and effectiveness of PD 325901 are greatly improved compared to PD 184352 (CI-1040). PD 325901 potently inhibited the growth of melanoma cells, with and without BRAF mutation. It also had an antiangiogenic activity. The sensitivity of RAS mutant cancers to MEK inhibitors depends on the activity of the phosphatidylinositol 3-kinase (PI3K) pathway. The antiproliferative effect on cancer cells of PD 325901 can be determined by a sensitive imaging biomarker, 3'-deoxy-3'-[18F]fluorothymidine-positron emission tomography ([18F]FLT-PET). PD 325901 potently inhibited the proliferation of thyroid cancer cells with an IC50 of 0.06-0.78 microM. It also has synergistic inhibitory effects when combined with phosphatidylinositol 3-kinase (PI3K) or NF-kB pathway inhibitors in most thyroid cancer cell lines. Blockade of MEK/ERK signaling by PD 325901 greatly enhances the cytotoxicity induced by arsenic trioxide (ATO) through a caspase-dependent mechanism in human myeloma cell lines and in tumor cells from patients with multiple myeloma. Melting Point: 116-118C Solubility: Soluble in DMSO at 12mg/ml; soluble in ethanol at 6.3mg/ml with slight warming; very poorly soluble in water; maximum solubility in plain water is estimated to be about 50-100uM; buffers, serum, or other additives may increase or decrease the aqueous solubility. Elemental Analysis: Calculated C - 39.85% H - 2.93% F - 11.82% I - 26.32% N - 5.81% Storage and Stability: Lyophilized powder may be stored at -20 degrees C. Stable for 12 months at -20 degrees C. Reconstitute with DMSO or ethanol. Aliquot to avoid repeated freezing and thawing. Store at -20 degrees C. For maximum recovery of product, centrifuge the original vial after thawing and prior to removing the cap. Further dilutions can be made in assay buffer.