生物活性

• 描述MEKs, short for MAPK/ERK kinases, involve two isoforms of MEK1 and MEK2. MEKs act as an integration point for multiple biochemical signals. MEKs lie upstream of MAPK/ERK and stimulate the enzymatic activity of MAPK/ERK upon wide variety of extra- and intracellular signals. As an essential component of MAPK/ERK signal transduction pathway, MEKs are involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. Refametinib is an inhibitor of MEK1/2. Refametinib inhibited MEK activity with IC₅₀ values of 19 nM and 47 nM for MEK1 and MEK2, respectively^[3]. Refametinib potently inhibited phosphorylation of ERK1/2 across several human cancer cell lines with EC₅₀ values ranging from 2.5 to 15.8 nM. Refametinib inhibited anchorage-dependent growth of human cancer cell lines with GI₅₀ values ranging from 67 to 89 nM^[3]. Refametinib also showed antiproliferative activity in HCC cell lines with IC₅₀s ranging from 33 to 762 nM^[4]. In an A375 tumor xenograft model established in nude mice, refametinib administrated orally at 25 or 50 mg/kg/d for 14 days inhibited 54% and 68% tumor growth, respectively. In a Colo205 tumor xenograft model established in nude mice, refametinib administrated orally at 2.5, 5, 10 or 25 mg/kg/d for 14 days inhibited 43%, 50%, 53% and 68% tumor growth, respectively^[3]. In an orthotopic murine Hepa129 HCC allograft model, treatment by refametinib at the dose of 25 mg/kg once daily (reduced to 12.5 mg/kg since day18) resulted in median survival of 58 days, compared with 30 days for the control group^[4].
• 作用机制Refametinib is a non–ATP-competitive inhibitor of MEK1/2. X-ray revealed that refametinib binds to an allosteric site of MEK without affecting ATP binding but precluding binding to the substrate ERK, thus preventing ERK phosphorylation^[3].