subject: The Function Of Pd0325901 In Mek1/2 [print this page] INTRODUCTION INTRODUCTION
Cancerous growth of cells is the net outcome of a number of mutations. Amongst the various pathways studied in this line, the most affected pathway during cancer has been found to be originating from Ras and moving down through Raf MEK(1/2) ERK(1/2). The ultimate activation of ERK1/2, leads to the phosphorylation of a number of substrates within the cytoplasm and nucleus. This generates different kinds of responses within the cells. Hence this pathway controls the cellular differentiation, cellular proliferation, cell death etc [1]. Out of the number of inhibitors which target this pathway, PD0325901 acts specifically at the stage of MEK1/2. PD0325901has proved to be a potent anticancer agent and has been experimented on xenograft models of human tumor.
CHEMISTRY OF THE MOLECULE
During the discovery of the molecules which target MEK in MAPK pathway, CI-1040 was discovered before PD0325901. CI-1040 has successfully crossed the phase I clinical trials, but could not prove its efficacy in Phase II. PD0325901 is a structural analogue of CI-1040 and was found to be a more potent inhibitor of MEK. It was found to be 500 times more potent than CI-1040. This inhibitor does not compete with ATP for its binding site hence acting as a non competitive inhibitor [2]. It was capable of inhibiting the MEK1 (MKK1) in its phosphorylated form, at a concentration of 1 M under in vitro conditions. However it bound with the un-phosphorylated form of MKK1 more strongly and hence it suppressed the activation of ERK1/ERK2. Growth factors like epidermal growth factor (EGF), stimulate the activation of ERK1/ERK2. This mode of activation was completely suppressed by PD0325901 [3].
PD0325901: ACTION ON ERK5
MKK5 is also a protein kinase which is related to another kinase that is MKK1. The inhibitors which can target MKK5 can also prevent the activation of ERK5 as ERK5 lies downstream to MKK5 and is a substrate of MKK5. The concentration of PD0325901 which effectively inhibits the activation of ERK1 or ERK2 is not sufficient for the inhibition of ERK5 activation. Hence they fail to inhibit the EGF stimulated activation of ERK5. This action was measured by measuring the electrophoretic mobility of the activated compound. At a higher concentration that is 2 M, this inhibitor was efficient to inhibit the phosphorylation of ERK5 [3]
PD0325901: EFFECT ON PTC
PTC or Papillary thyroid carcinoma is the most common type of cancer affecting the thyroid glands. PTC is the net outcome of two mutations that is mutation of the BRAF gene and rearrangement of RET/PTC. Out of the various ways in which BRAF gets mutated, one common method is by substitution of thymine with Adenine at 1799 position. This position lies in the 15nth exon and after translation it leads to the conversion of the amino acid val to Glu. This takes place at codon number 600 and this conversion is denoted as (V600E) within the BRAF protein. The glutamic acid carries a negative charge and shows an effect similar to phosphorylation at a site nearby to it during the BRAF activation [4]. The RET/PTC rearrangements are due to the generation of fused (chimeric) oncogenes. These oncogenes have H4 gene fused with the kinase domain from RET. Together the fused oncogene is known as RET/PTC1 [5]. Similarly there are other chimeric oncogenes also known as RET/PTC2, and RET/PTC3. Both The BRAF mutation and the rearrangement activate MEK1/2. PD0325901 was effective in the cell lines which showed both the mutation and rearrangement.
CONCLUSION
To summarize PD0325901 is a potent and selective inhibitor of MEK1/ MEK2. It has also proved its action against phosphorylation of ERK5 in cell based assays.
REFERENCES
1. Fremin C, Meloche S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol 2010 Feb 11; 3:8.
2. Judith S. Leopold S, et al. The biological profile of PD 0325901: A second generation analog of CI-1040 with improved pharmaceutical potential. Proc Amer Assoc Cancer Res 2004; 45.
3. Bain J, Plater L, et al. The selectivity of protein kinase inhibitors: a further update.
4. Wojciechowska K, Lewinski A. BRAF mutations in papillary thyroid carcinoma. Biochem J 2007 Dec 15; 408(3):297-315. Endocr Regul 2006 Dec; 40(4):129-38.
5. Grieco M, Santoro M, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 1990 Feb 23; 60(4):557-63.
