We describe the mechanism of action of WP1130

by Selleckchem | Jan 22 2014

The ras/raf/MEK/ERK pathway is activated in many strong tumors. Several different events are capable of inducing ras into its GTP bound, energetic state. ras recruits raf, a serine/threonine kinase that in turn phosphorylates mitogen activated protein kinase kinases 1 and two. MEK1/2 are threonine/tyrosine protein kinases and their only acknowledged phosphorylation targets are extracellular signal-regulated kinases 1 WP1130 and 2. ERK1/2 phosphorylate a few nuclear proteins, resulting in proliferation and migration. This pathway is felt to become significant in many malignancies, including NSCLC and breast cancer. In NSCLC, this pathway is activated by ras mutations in 20?C30% of cases. Mutations in ras are associated with poor prognosis and resistance to epidermal development component receptor inhibitors. Mutations in ras and raf are significantly less widespread in breast cancer, with an incidence of 4% and 7% respectively. Laboratory information signifies that mutations in ras or raf in NSCLC and breast cancer, specifically the non-luminal subtype are associated with response to MEK inhibition. Given specific and potent inhibition of MEK with offered pharmacologic agents, most laboratory based mostly publications have relied on MEK inhibitor to assess pathway PARP addiction. Other procedures such as inhibition via siRNA, have yielded results much like those seen with pharmacologic MEK inhibition. The PI3K/AKT/mTOR pathway is a vital option downstream pathway which has become hypothesized to provide an escape mechanism for some cell lines to MEK inhibition. PI3K pathway activation is proven to predict resistance to MEK inhibition in ras mutants. In vivo and in vitro models demonstrated that combined inhibition of MEK and PI3K pathways enhanced apoptosis in lines resistant to MEK inhibition alone, particularly in cell lines with each ras and PI3K pathway mutations. In vivo combination of the PI3K/mTOR inhibitor in addition to a MEK inhibition in ras mutant tumors demonstrated synergy. The initial MEK-inhibitor to enter clinical trials was CI-1040, an oral small molecule inhibiting MEK 1/2. In a phase I clinical trial enrolling 66 patients, 1 partial response was seen within a patient with pancreatic cancer, and 19 patients knowledgeable steady condition. These encouraging effects were evaluated inside a phase salubrinal II research of unselected individuals with NSCLC, breast cancer, colon cancer and pancreatic cancer. Effects were less robust, without any goal responses in 67 patients, and steady disorder in only eight sufferers. Selumetinib is usually a second-generation MEK inhibitor presently in clinical development. It is a potent, tight binding, uncompetitive MEK inhibitor with an IC50 of 14nM against purified MEK1. To test the hypothesis that a subgroup of human breast cancer cell lines and NSCLC cell lines would be much more sensitive to MEK inhibition by selumetinib, we carried out a series of pre-clinical studies in large panels of molecularly characterized human cell lines from each histologies.