Role of PD0325901 in MEK1/2, kinase inhibitor, compound libraries

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Role of PD0325901 in MEK1/2, kinase inhibitor, compound libraries

Posted On : Jan-18-2012 | seen (567) times | Article Word Count : 628 |

INTRODUCTION

Various mutations are mainly the cause cancer or tumor growth. A good number of pathways have been studied so far in order understand the mechanism of cancer growth and proliferation. Among these pathways the most important one is the Ras originated and to downstream Raf-MEK1/MEK2-ERK1/ERK2. The stimulation of ERK1/2 results in activation of various substrates upon phosphorylation in cell nucleus or cytoplasm and this ultimately leads to the multiple responses in the cell. So this pathway is important in the cell growth, proliferation and differentiation as well as cell death [1]. There a good number of inhibitors are present in the compound libraries which act as MAP kinase inhibitor. PD0325901 is one of these inhibitors which can target this vital pathway at MEK1/2 stage. Various human xenografts models have been analyzed in order to find the effects of PD0325901; it was proved as strong anti-cancer compound.

Discovery of CI-1040 was prior to the PD0325901 during the designing of various compounds which could target MEK during the MAP kinase pathway. CI-1040 has efficiently crossed the clinical trials phase I but unfortunately it was unable to pass through the phase II trials. PD0325901 is a CI-1040 analogue and it has proven as a strong MEK inhibitor. It is reported that this inhibitor is 500 times more strong than CI-1040. It is a non-competitor inhibitor as it does not affected by the presence of ATP (adenosine triphosphate) a natural substrate of MEK [2]. During in-vivo conditions when a 1 µM concentration of this compound was used the phosphorylated form of MEK (MKK1) was inhibited. In some of the experiments it was noticed that this inhibitor can also inhibit the un-phosphorylated MKK1 more strongly, proving its efficacy in ERK1/2 inhibition. Epidermal growth factor or EGF activates the ERK1/2. This mechanism of action was completely suppressed due to PD0325901 [3].

Another protein kinase known as MKK5 is related to MKK1 another kinase. The ERK5 activation can also be targeted by using MKK5 inhibitors as the ERK is substrate of MKK5 and present downstream to this MKK5. PD0325901 could not inhibit the MKK5 when a same concentration was used at which the ERK1/2 are inhibited effectively. Hence they were unable to inhibit the activity of ERK5 stimulated by EGF. This activity was analyzed using gel electrophoresis and by noticing the mobility of active proteins. However when a 2 µM concentration of this compound was utilized it was noticed that the ERK5 phosphorylation was inhibited significantly [3].

Papillary thyroid carcinoma or PTC is as the most widely found cancer type which affects the thyroid glands. In case of PTC, there are two types of mutations are mainly found, the rearrangement of PTC/RET and secondly BRAF gene mutation. Amongst a large number of mutation causes, the one of the most common is the found at the 1799 position where Adenine is replaced by Thymine. This position is on 15th exon and this muted gene codes for glutamic acid instead of valine. This conversion is represented as V600E in B-Raf protein and is present on 600 codon number. This glutamic acid performs a similar function in BRAF activation as the phosphate group does due to its negative charge [4]. The fused or chimeric oncogenes are the cause of RET/PTC rearrangement. The H4 gene is also fused with kinase gene and these fused genes are called as RET/PTC1 [5]. The RET/PTC2 and RET/PTC4 are also present. PD0325901 was found as very efficient in the inhibition of these mutated genes and can also be used with other apoptosis inhibitors.

CONCLUSION

In a nut shell, PD0325901 was found as selective for MEK1/2 during the compound library screening. Various cell based experiments also have proven its efficacy against ERK5 phosphorylation.

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<h1>Role of PD0325901 in MEK1/2, kinase inhibitor, compound libraries</h1> Author: <a href='http://www.articleseen.com/profile_Dr.Rabia.aspx'>Dr.Rabia</a> INTRODUCTION

Various mutations are mainly the cause cancer or tumor growth. A good number of pathways have been studied so far in order understand the mechanism of cancer growth and proliferation. Among these pathways the most important one is the Ras originated and to downstream Raf-MEK1/MEK2-ERK1/ERK2. The stimulation of ERK1/2 results in activation of various substrates upon phosphorylation in cell nucleus or cytoplasm and this ultimately leads to the multiple responses in the cell. So this pathway is important in the cell growth, proliferation and differentiation as well as cell death [1]. There a good number of inhibitors are present in the compound libraries which act as MAP kinase inhibitor. PD0325901 is one of these inhibitors which can target this vital pathway at MEK1/2 stage. Various human xenografts models have been analyzed in order to find the effects of PD0325901; it was proved as strong anti-cancer compound.

Discovery of CI-1040 was prior to the PD0325901 during the designing of various compounds which could target MEK during the MAP kinase pathway. CI-1040 has efficiently crossed the clinical trials phase I but unfortunately it was unable to pass through the phase II trials. PD0325901 is a CI-1040 analogue and it has proven as a strong MEK inhibitor. It is reported that this inhibitor is 500 times more strong than CI-1040. It is a non-competitor inhibitor as it does not affected by the presence of ATP (adenosine triphosphate) a natural substrate of MEK [2]. During in-vivo conditions when a 1 µM concentration of this compound was used the phosphorylated form of MEK (MKK1) was inhibited.  In some of the experiments it was noticed that this inhibitor can also inhibit the un-phosphorylated MKK1 more strongly, proving its efficacy in ERK1/2 inhibition. Epidermal growth factor or EGF activates the ERK1/2. This mechanism of action was completely suppressed due to PD0325901 [3].

Another protein kinase known as MKK5 is related to MKK1 another kinase.  The ERK5 activation can also be targeted by using MKK5 inhibitors as the ERK is substrate of MKK5 and present downstream to this MKK5. PD0325901 could not inhibit the MKK5 when a same concentration was used at which the ERK1/2 are inhibited effectively. Hence they were unable to inhibit the activity of ERK5 stimulated by EGF. This activity was analyzed using gel electrophoresis and by noticing the mobility of active proteins. However when a 2 µM concentration of this compound was utilized it was noticed that the ERK5 phosphorylation was inhibited significantly [3].

Papillary thyroid carcinoma or PTC is as the most widely found cancer type which affects the thyroid glands. In case of PTC, there are two types of mutations are mainly found, the rearrangement of PTC/RET and secondly BRAF gene mutation. Amongst a large number of mutation causes, the one of the most common is the found at the 1799 position where Adenine is replaced by Thymine. This position is on 15th exon and this muted gene codes for glutamic acid instead of valine. This conversion is represented as V600E in B-Raf protein and is present on 600 codon number. This glutamic acid performs a similar function in BRAF activation as the phosphate group does due to its negative charge [4]. The fused or chimeric oncogenes are the cause of RET/PTC rearrangement. The H4 gene is also fused with kinase gene and these fused genes are called as RET/PTC1 [5]. The RET/PTC2 and RET/PTC4 are also present. PD0325901 was found as very efficient in the inhibition of these mutated genes and can also be used with other apoptosis inhibitors.

CONCLUSION

In a nut shell, PD0325901 was found as selective for MEK1/2 during the compound library screening. Various cell based experiments also have proven its efficacy against ERK5 phosphorylation.

About the Author: We has established long-term and stable relationships with more than 10,000 customers from pharmaceutical and biotech companies, universities and research institutions. We have high quality inhibitors like <a rel="nofollow" href="http://www.selleckchem.com/products/Neratinib(HKI-272).html">HKI-272</a>, <a rel="nofollow" href="http://www.selleckchem.com/products/GSK690693.html">GSK690693</a>, <a rel="nofollow" href="http://www.selleckchem.com/products/Neratinib(HKI-272).html">Neratinib</a> & more. Article Source: <a href='http://www.articleseen.com/Article_Role-of-PD0325901-in-MEK1-2-kinase-inhibitor-compound-libraries_135914.aspx'> http://www.articleseen.com/Article_Role of PD0325901 in MEK1/2, kinase inhibitor, compound libraries_135914.aspx</a>

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We has established long-term and stable relationships with more than 10,000 customers from pharmaceutical and biotech companies, universities and research institutions. We have high quality inhibitors like HKI-272, GSK690693, Neratinib & more.

Keywords : Neratinib, GSK690693,

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