CHEMISTRY OF AZD8330
AZD8330 is alternatively known as AZD-8330; ARRY-424704; ARRY-704. Chemically this molecule is mitogen-activated protein kinase kinase 1/2 which arecreatedbecause of thisof the expression with the MAP2K1/MAP2K2 genes respectively. They are dual certain kinases plus avital component with the MAPK signaling pathway (Ras ¡§C Raf ¡§C MEK ¡§C ERK). This pathway plays a important role in controlling tumor cell growth, cellular differentiation and angiogenesis that is growth of blood vessels from previously existing vessels [1].
The small molecule AZD8330 shows a non competitive inhibition of MEK1/2. It does not compete with ATP for its binding website. The levels of phosphorylated MEK1/2 changein the case of cancer cell lines. This inhibitor targets these fluctuations. It also controls the boostin the phosphorylation of MEK1/2 by the feed back mechanism. It does nothave an effect on the other kinases showing its specificity in action. It is undergoing phase I clinical trails to prove its efficacy.
AZD8330: ROLE IN EGFR INDUCED CASCADE
The Raf mutations have been largely related to the cancer cells. The serine/threonine kinase enzymes produced by the expression of Raf gene activate MEK1/2 protein kinases. These kinases in turn activate ERK1/2. This entire pathway originating from Raf lies downstream to Ras. The Ras gene is also mostly subjected to mutations in case of several cancers. The Ras gene is itself controlled by EGFR (epidermal growth factor receptor). Experiments have shown that EGFR gene is mutationally activated or from time to time overexpressed in case of cancerous circumstances. The downstream effector of this pathway, ERK regulates the EGFR expression by the feed back mechanism. It stimulates the overexpression of EGFR ligands [2][3]. This promotes the EGFR autocrine loop which isreallyessential for the growth of tumors. AZD8330 specifically targets the EGFR induced activation of MEK1/2 hence controlling the tumor cell proliferation. As ERK is the only substrate for MEK1/2, the latter serve as effective targets for inhibition. This inhibitor is efficient at low nanomolar concentrations ( Paclitaxel), thereforecreating it a lot morepopular [2].
AZD8330: ROLE IN APOPTOSIS
A bigquantity of experiments have shown that when ERK1/2 pathway gets activated it prevents the regular apoptosis. The mechanism behind this getting withdrawal of growth factor. Experiments using the cultured cells have also shown the deprivation of matrix attachment and linked cytoskeletal disruptions [3]. The specific inhibitors of MEK1/2 like AZD8330 decrease the levels of MEK1/2 thereforetop to cell death [4].
CONCLUSION
The levels of MEK1/2 could be regulated using siRNA or specific chemical agents which act as inhibitors. AZD8330 can control the Ras mutational effects also. Though AZD8330 is still undergoing clinical trials it is actuallyregarded as to be a promising candidate to check the MAPK pathway at the stage of MEK1/2.
AZD8330 is alternatively known as AZD-8330; ARRY-424704; ARRY-704. Chemically this molecule is mitogen-activated protein kinase kinase 1/2 which arecreatedbecause of thisof the expression with the MAP2K1/MAP2K2 genes respectively. They are dual certain kinases plus avital component with the MAPK signaling pathway (Ras ¡§C Raf ¡§C MEK ¡§C ERK). This pathway plays a important role in controlling tumor cell growth, cellular differentiation and angiogenesis that is growth of blood vessels from previously existing vessels [1].
The small molecule AZD8330 shows a non competitive inhibition of MEK1/2. It does not compete with ATP for its binding website. The levels of phosphorylated MEK1/2 changein the case of cancer cell lines. This inhibitor targets these fluctuations. It also controls the boostin the phosphorylation of MEK1/2 by the feed back mechanism. It does nothave an effect on the other kinases showing its specificity in action. It is undergoing phase I clinical trails to prove its efficacy.
AZD8330: ROLE IN EGFR INDUCED CASCADE
The Raf mutations have been largely related to the cancer cells. The serine/threonine kinase enzymes produced by the expression of Raf gene activate MEK1/2 protein kinases. These kinases in turn activate ERK1/2. This entire pathway originating from Raf lies downstream to Ras. The Ras gene is also mostly subjected to mutations in case of several cancers. The Ras gene is itself controlled by EGFR (epidermal growth factor receptor). Experiments have shown that EGFR gene is mutationally activated or from time to time overexpressed in case of cancerous circumstances. The downstream effector of this pathway, ERK regulates the EGFR expression by the feed back mechanism. It stimulates the overexpression of EGFR ligands [2][3]. This promotes the EGFR autocrine loop which isreallyessential for the growth of tumors. AZD8330 specifically targets the EGFR induced activation of MEK1/2 hence controlling the tumor cell proliferation. As ERK is the only substrate for MEK1/2, the latter serve as effective targets for inhibition. This inhibitor is efficient at low nanomolar concentrations ( Paclitaxel), thereforecreating it a lot morepopular [2].
AZD8330: ROLE IN APOPTOSIS
A bigquantity of experiments have shown that when ERK1/2 pathway gets activated it prevents the regular apoptosis. The mechanism behind this getting withdrawal of growth factor. Experiments using the cultured cells have also shown the deprivation of matrix attachment and linked cytoskeletal disruptions [3]. The specific inhibitors of MEK1/2 like AZD8330 decrease the levels of MEK1/2 thereforetop to cell death [4].
CONCLUSION
The levels of MEK1/2 could be regulated using siRNA or specific chemical agents which act as inhibitors. AZD8330 can control the Ras mutational effects also. Though AZD8330 is still undergoing clinical trials it is actuallyregarded as to be a promising candidate to check the MAPK pathway at the stage of MEK1/2.