MEK kinases are central components of diverse intracellular signaling pathways. MEK1 and MEK2 specifically act downstream of growth factor receptors and the proto-oncogenes Ras and Raf to activate ERK1 and ERK2, often leading to an increase in cell proliferation. AZD 6244 is a potent, highly selective inhibitor of MEK1 and MEK2 (IC50 = 14 and 530 nM, respectively). It weakly inhibits the EGF receptor (IC50 = 7.0 μM) and has no effect on a large panel of other kinases. AZD 6244 suppresses the growth of tumors displaying high levels of phosphorylated MEK1/2 or ERK1/2. In addition to suppressing growth, it induces apoptosis and differentiation within tumors. AZD 6244 has potential, alone or in combination therapy, for promoting tumor regression in various forms of cancer, including those involving mutations of the proto-oncogenes Ras and Raf.
