As703026 Is An Important Agent Against Cancer Cells

INTRODUCTION

The signaling pathways that are mediated by various growth factors and tumor cell proliferation have an important role of MEK1 and MEK2 enzymes which are kinase activator enzymes (kinases). These enzymes have dual specificity that is phosphorylation of tyrosine and threonine amino acids along with the activation of RAF/RAS/ MRK/ERK pathway. Cancerous cells mostly have high expression of these kinases. Like U0126, AS703026 is an inhibitor of these kinases (kinase inhibitor) regulating the expression of these enzymes ultimately controls the down-stream signaling pathways and prevents the growth of tumors and cancerous cells.

MECHANISM OF ACTION

AS703026 is not only a non-competitive kinase inhibitor but it is also very specific for MEK1/2. Like different other inhibitors for example, cal-101 and AZD2171 this inhibitor has passed through preclinical trials and now it is under phase I clinical trials. The purpose of these clinical studies is to monitor the highest tolerated dose of this inhibitor along with the other pharmacokinetics studies. In different studies it has been reported that a concentration from 0.005 to 2 M of this inhibitor effectively suppresses the growth of tumor and the cancer cells. In addition to that clinical studies have proven the good safety of this drug with pharmacokinetic studies. This compound resulted in complete inhibition in peripheral blood mononuclear cells (PBMCs) at about the doses 28 mg per day [1].

EFFECT ON CANCEROUS CELLS

Mutated forms of KRAS (Kirsten ras sarcoma viral oncogene) or BRAF (B-type Raf kinase) continuously activates the signaling pathways of MEK1/2 followed by ERK1/2. Mutations of these genes are generally found in colorectal cell lines due to which the ERK1/2 is activated following the activation of PI3K pathway. Inhibitors of MEK1/2 are also very efficient in those cells which have high levels of ERK1/2 [2].

This inhibitor is found to be more potent than AZD6244 because it can control the differentiation of osteoclasts in a much better way. AS703026 is also tested for the human multiple myeloma (MM) and found to be very effective. It inhibited the growth as well as multiple myeloma cells survival. It is reported that AS703026 inhibited the MAF oncogene expression and arrested the cell cycle at G0-G1 phase. It was also found that it is the inducer of apoptosis by cleavage of caspase 3 and Poly adenosine diphosphate ribose polymerase (PARP). Moreover at the concentration of