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Blog of Signaling Pathways

HISTONE DEACETYLASE INHIBITORS – CANCERS AND BEYOND

3955 views | Jun 26 2012

HDAC INHIBITIORS AND EPIGENEITIC MODULATION: Histone proteins are major part of cellular genome and acetylation of these proteins plays a mile stone role in some of the most important cellular mechanisms such as growth of cell and cell death by apoptosis. The process which controls apoptosis process is carried out by checking the gene transcription of different important proteins by removing acetyl groups from histones, this deacetylation leads to condensation of DNA due to increasing capacity of DNA binding. In neurodegenerative diseases this mechanism of deacetylation goes wrong leading to various types of cancers in which cell proliferation is uncontrolled. This problem leads to the HDAC inhibitor pathway and smoothes the process of HDAC inhibition. HDAC inhibitions have been employed in preclinical and clinical studies due to which extensive and successful use of this process is targeted by many researchers. HDACs levels estimation has been developed by different activity assays. These assays are carried out by manually in the research lab or by kit methods. A nonisotopic assay that is microplate reader compatible can also be performed by researchers for the analysis of HDAC inhibitors, an appropriate test for compound profiling and robotic screening or a suitable fluorescence assay for high-throughput screening. [Read the Full Post]

PARP INHIBITOR: ISCHEMIA, STROK AND CANCER

3753 views | Jun 24 2012

PARP CASCADE DEREGULATION AND ITS IMPLICATION: PARP are Poly ADP-ribose polymerases and translated by PARP genes present in human genome. These proteins are important for the regulation of critical processes such as DNA repair mechanism and programmed cell death. The DNA repair mechanism based on these enzymes is specific for ssDNA (single stranded DNA) breaks. A sufficient data is available on the BRCA1 and BRCA2 interaction which leads to the concept of PARP deregulation link with breast and ovarian cancer because many cases of these cancers reported about the mutations present in these two genes. Because of this reason PARP inhibition mechanism has proved as an effective therapeutic tool [1] where inhibitors specific for PARP may have effective results against cancers and tumors with BRCAness. PARP inhibitors are mostly specific as the tumor cells are targeted by these molecules therefore the normal cells remain un-affected. The mechanism of PARP inhibitor is so effective against cancer and due to this reason conventional therapies are becoming less useable due to their effects on healthy cells as well. [Read the Full Post]

DASATINIB; A Receptor Tyrosine Kinase inhibitor

3856 views | Jun 25 2012

PROPERTIES OF DASATINIB Researchers and scientists are trying hard to find a better drug with good efficiency because cancer has become the cause of huge deaths all over the world and secondly resistance to the available drugs in cancer cells is increased. Cancer cells evade the action of particular medicine to become resistant by mutating themselves in a number of ways. Metastasis is also another problem related to cancer. For chemotherapy of cancer cell toxicity adds to the problem. To combat these afore mentioned difficulties it is necessary as well as mandatory to devise new medicines. Imatinib was given for years but due to its toxicity and other effects mentioned above it forced scientists to develop a less toxic and more efficient medicine. So in this regard Jagabandhu Das developed a new medicine called Dasatinib. Dasatinib BMS 354825 got very popular as compared to Imatinib because of its lesser toxicity and more efficiency.It is developed by a pharmaceutical company Squibb and marketed under the trade name of Sprycel. [Read the Full Post]

BORTEZOMIB: AN ANTI-PROTEIN DEGRADATION AGENT

4289 views | Jun 20 2012

BORTEZOMIB Proteasomes belong to one of the important small organelles present in cell. Cell cycle is regulated by these proteasomes as they remove any unnecessary protein from cell. Usually during the cancer state the proteins which inhibit uncontrolled cell development of cancer are chopped down by these proteasomes. To stop chop these abnormal proteins properly inhibition of proteasomes is necessary which offers a good target for cancer therapy. For cancer treatment a lot of various compounds are being employed that cause proteasomes inhibition for example e.g., green tea having Epigallocatechin-3-gallate (EGCG), Salinosporamide-A and Disulfiram. Bortezomib was entitled to be first inhibitor that got approval to enter clinical studies for treatment of cancer. [Read the Full Post]

ERLOTINIB– THE HCL SALT

4816 views | Jun 19 2012

ERLOTINIB AND ITS PROPERTIES Erlotinib comes under the category of tyrosine kinase inhibitorswhich is also called OSI-420 EGFR inhibitor and usually named as HCl salt. Epidermal growth factor tyrosine kinase receptor is usually seen abnormal in various types of cancers so they are being employed for the anti-cancer therapy. A lot of new medicines are being produced by using the same approach [1]. Erlotinib structure revealed that it contained two quinazoline rings in its structures and it showed to inhibit the EGFR auto phosphorylationwhich eventually stops the pathway which is involved in the overexpression of genes. Around 18mg/ml in dimethyl sulfoxide (DMSO) is the Erlotinib solubility however it is scarcely soluble in water and ethanol. For inhibition of EGFR 20nM is Erlotinib IC50 [2]. It is easily oxidize able so care must be taken to increase its shelf life. Approximately $65 per 1000mg is Erlotinib price and buy OSI-420 for any kind of purpose under this trade name. [Read the Full Post]

SUNITINIB-AN INHIBITOR OF RECEPTOR TYROSINE KINASE

2790 views | Jun 18 2012

A CHEMOTHERAPEUTIC AS MULTIKINASE INHIBITOR Tyrosine kinases are the enzymes which act as mediators between different cells to facilitate variety of metabolic processes in cells. Since these tyrosine kinases play important role in processes e.g. division, survival, multiplication, differentiation, growth and death of cell, their inhibition have been found very promising target. Any type of modulation of these enzymes can cause the downstream regulation of the pathways controlled by them. This behaviour is being exploited as inhibitors of tyrosine kinases for chemotherapy. Many tyrosine kinase inhibitors are multi kinase inhibitors as they can inhibit more than one type of tyrosine kinase enzymes. VEGF pathway involvement in breast carcinoma and some other tyrosine kinases in other cancers made these enzymes a popular interest. Different types of carcinomas are being successfully treated by using inhibitors of tyrosine kinase. [Read the Full Post]

SUNITINIB-AN RTK INHIBITOR

2920 views | Jun 17 2012

MULTIKINASE INHIBITORS AND CHEMOTHERAPY A variety of cell signalling pathways are there in the cellular systems of the body that govern different cellular processes in the cells. Tyrosine kinase pathways are one of these pathways that play role in growth, proliferation, survival and apoptosis etc. Overexpressed tyrosine kinases may hence lead to cancer and is amongst the major reasons in most of the cancer conditions. Inhibition of tyrosine kinases is hence being done by using different types of tyrosine kinase inhibitors. A single inhibitor may sometimes block multiple kinases in one time. The examples of cancers involving tyrosine kinase defects is breast cancer in which VEGF pathway is disturbed. Various kinds of carcinomas involving such defects are being treated using these tyrosine kinase inhibitors for example gastrointestinal stromal tumors and Acute Lymphoblastic Leukaemia (ALL).  [Read the Full Post]

TEMSIROLIMUS

2474 views | Jun 11 2012

TEMSIROLIMUS: mTOR INHIBITOR Protein kinase mTOR are the enzymes that come under the category of phosphatidylinositol 3-kinase or PI3-K that control the cell migration, cell multiplication, cell transcriptional and translational actions and cell survival. The fact that these inhibitors are involved in the above described processes, these enzymes have come into lime light for cancer therapy. In the recent years Temsirolimus mTOR inhibitor has got more popularity as compared to Rapamycin which was used in the late years. [Read the Full Post]

NILOTINIB AND PH+

5554 views | Jun 10 2012

PHILADELPHIA CHROMOSOME AND CML Philadelphia chromosome is formed by fusion of a tyrosine kinase ABL (Abelson) and BCR (break point cluster) gene during the cross linking of chromosomes in meiosis. This Philadelphia chromosome gives rise to a fusion protein that is functions in an uncontrolled manner as a tyrosine kinase making it an oncoprotein. This fusion oncoprotein is involved in causing CML i.e., chronic myelogenous leukemia in 90 % of patients of this disease. Due to the involvement of this fusion protein in CML, it is being targeted in lots of research going on for cancer therapeutics. Nilotinib bcr-abl inhibitor is one these inhibitors being used against CML. [Read the Full Post]

SORAFENIB-AS A MULTIKINASE INHIBITOR

3136 views | Jun 08 2012

SORAFENIB For receiving extracellular or intracellular stimulus numerous types of non-receptor and receptor tyrosine kinases are present in cells which are capable of conducting inhibitory and initiatory action on different signalling pathways. Defect of any type in these processes can cause cancer. The kinases which are involved in the over-expression or under expression of gene that are cause of cancer can be used as target for cancer therapy. Different types of kinases are being inhibited by employing only one inhibitor. Due to the involvement of abnormal tyrosine kinase in the development of cancer inhibitors of tyrosine kinases are being developed and studied to use it as for the treatment of cancer. Clinical trials of different inhibitors have shown outstanding results. Among these inhibitors one important inhibitor is Sorafenib inhibitor which has shown to inhibit kinases excluding respective VEGFR. Similarly Raf pathway/ERK/MEK pathway have been found inhibited by the administration of Sorafenib Raf inhibitor. [Read the Full Post]

ROLE OF HIGH THROUGHPUT SCREENING IN DRUG DISCOVERIES

3099 views | Jun 07 2012

INTRODUCTION: High throughput screening is one of the novel and leading technique for the discoveries of new pharmaceutical agents for the treatment of various lethal diseases. This famous technique is also called as the High throughput screening assay, this technique has been so impressive and fast due to the advancements in automatic machines. This technique is based on the properties of different chemical agents for their ability under pharmaceuticals, biochemical and biological actions against any disorder. In the era of drug discovery this technique has been proved as the most effective for the treatment of specific diseases and these treatments are based on the drugs discovered as ligands for receptors, enzymes, proteins and ion channels. High throughput screening is also used for the detection and study of cellular or biochemical pathways for the assessment of the certain therapeutics for respective cellular mechanisms. The major example includes screening library of kinases and this is leading applied example in this regard in comparison to old methods. The importance of High throughput screening can be analyzed by studying reviews of this novel method for discovering new drugs. Business of pharmaceuticals and science and research has been greatly benefited by this method. [Read the Full Post]

PAZOPANIB: LATEST VEGFR INHIBITOR

3332 views | Jun 06 2012

PAZOPANIB: INTRODUCTION One of the very important anti-tumor drugs Pazopanib VEGFR inhibitor also known as Pazopanib Votrient is being produced by the very popular pharmaceutical company which is GlaxoSmithKline. It is selling this drug with commercial name of Votrient. Pazopanib inhibits the angiogenesis by blocking VEGF R1, R2 and R3 with their β subtypes and also inhibits c-kit RTKs as well as PDGFR-a. Though Pazopanib is tiny molecule yet it gains popularity due to its extensive potential on various kinds of malignancies. PazopanibVEGFR-PDGFR inhibitor has now been approved to enter the clinical trials. It was revealed by the Pazopanib structure that it contained a sulfonamide group. It is marketed in 25mg of packaging with Pazopanib price of approximately $100 as Votrient or GW786034 and anyone can buy Pazopanib for research or experimental purposes from supplier Pazopanib. Prices are being varied from supplier to supplier. Pazopanib solubility revealed it is best soluble in DMSO while it is absolutely insoluble in water and ethanol. [Read the Full Post]

EVEROLIMUS-AN mTOR INHIBITOR

2644 views | Jun 05 2012

mTOR PATHWAY AND EVEROLIMUS Regulatory activities of the cell that are related to its multiplication, movement, transcription and as well as translation of the genes is controlled by mTOR pathway which is one of the important various cell cycle regulators. FRAP1 gene is translated to produce mTOR which phosphorylates serine/threonine residue of proteins. Cancer usually arises from the down-regulation of this mTOR cascade. So for targeted cancer therapy proteins like it are also taken under consideration [1].Different types of inhibitors are being searched and Everolimus mTOR inhibitoris one of the very promising inhibitors [2]. Novartis which is pharmaceutical company produced it and sell it with as Afinitor Everolimus which is its trade name. Since structural studies revealed that Everolimus is a derivative of 40-O-(2-hydroxyethyl), the pharmacokinetic properties are seemed to be improved due to the availability of oxygen atom the 40 position. Against mTOR Everolimus IC50 is approximately 1nM.Around 100mg/ml of DMSO is suitable for Everolimus solubility. It is water and ethanol soluble. The mode of administration of Everolimus is through oral route and it is present in 5mg of packaging and approximately $60 is Everolimus price. Dry-ice is used for its distribution. [Read the Full Post]

DASATINIB- A DRUG OF CHOICE

5753 views | Jun 04 2012

INTRODUCTION Diverse types of cellular systems are there in human bodies that differ structurally and functionally from one another. Each cellular system is controlled by a variety of controllers called cell cycle regulatory proteins. Defective controllers may lead to abnormal cellular systems and the condition known as cancer may develop. Cancer may be of different types depending upon the defect in the cell cycle regulatory proteins. Cancer may also vary on the basis of stage of the defective condition. Many therapies have been devised in order to treat cancerous cells. Further research is also being done for developing better, more specific and less toxic therapies and to cope with the development of resistance in the defective cells against existing therapies. Besides resistance, metastasis is also another issue to be resolved in case of cancerous cells. Imatinib has been used against leukemia for several years but due to high levels of toxicity scientists discovered a new drug, called Dasatinib, for the same therapy. Dasatinib BMS-354825 is more efficient and less toxic as compared to Imatinib. The drug is being marketed by the name of Sprycel. As Dasatinib was discovered by Jagabandhu Das, it was named Dasatinib. Development of the drug was done by Squibb Company. [Read the Full Post]

RALTEGRAVIR- FAMOUS INTEGRASE INHIBITOR

3399 views | Jun 03 2012

INTEGRASE IN CASE OF HIV-1 The most deathly disease on earth, HIV-I, is being researched and studied a lot to find out an effective therapy against it. This virus contains some genes for enzymes/proteins and utilizes some others from the host cells. The enzyme in HIV that helps the virus to integrate its genome into host cell/genome is named as Integrase and gets replicated there. To search for the [roper treatment the first thing that must be keep in mind is resistance development by the mutation of their genes during replication, so it is the need of hour that the research about treatment of cancer must go on further and should be regularly updated. To inhibit their enzymatic activity is an attractive approach. The inhibitors for integrase enzyme have been developed and they inhibit the process of integration of viral genome into the host genome hence prevent its proliferation in the hosting cell. A huge wave of research is going on HIV-I regarding integrase inhibitors that offer promising results against HIV-I virus. Raltegravir integrase inhibitor is such an inhibitor that inhibits the integrase enzyme and it is the first inhibitor to get approved from FDA and its discovery is no doubt considered to be a great blessing. [Read the Full Post]

NILOTINIB

5691 views | May 30 2012

ROLE OF BCR-ABL TYROSINE KINASES IN CML: A chimeric BCR-ABL oncogene is obtained by the fusion of Abelson (ABL) tyrosine kinase (TK) gene and break-point cluster (BCR) gene, and here TK has been related to pathogenesis of CML (Chronic Myelogenous Leukemia), 90% of this debilitating disease involves chromosomal abnormalities leading to formation of so-called Philadelphia chromosome. As there is a confirmed participation of BCR-ABL TK in PH+ CML, different inhibitors that target this TK have registered remarkable success in treatment of CML and among them Nilotinib bcr-abl inhibitor is the most valuable one. It is a form of tyrosine kinase inhibitor and is a hydrochloride monohydrate salt. [Read the Full Post]

SUNITINIB: THE MULTI-TARGETED APPROACH

2805 views | May 31 2012

MUTIKINASE INHIBITORS IN CHEMOTHERAPEUTICS:  Different types of metabolic systems that occur between varieties of cells are mediated through a class of enzymes called tyrosine kinases. Since these tyrosine kinases play important role in processes e.g. division, survival, multiplication, differentiation, growth and death of cell, their inhibition have been found very promising target. By doing any change in them the processes which they regulate can also be down regulated. This behaviour is being exploited as inhibitors of tyrosine kinases for chemotherapy. The inhibitors of tyrosine kinases block multiple kinases at the same time. The involvement of tyrosine kinases in the pathways which cause different cancers like it is involved in vascular endothelial growth factor pathway in case of breast cancer and many other types of cancer makes them interesting. [Read the Full Post]

RAD001 – THE mTOR INHIBITOR

2749 views | May 29 2012

RAD001: The mTOR protein which is also known as Rapamycin’s mammalian target protein is famous threonine or serine protein kinase enzyme. This kinase plays several significant roles including cellular survival, cell division, migration of cells and also in regulating a good numbers of transcriptional events linked to a huge number of signaling cascades such as aging. There are several research reports mentioning the involvement of abrupt mTOR pathway in cancer and tumorigenesis, due to this fact this pathway has become a target for the cure of large number of cancers [1]. Different mTOR inhibitors has been generated and tested, amongst these inhibitors RAD001 mTOR inhibitor is orally bio-available chemical [2]. This is developed by Novartis and is recognized under the name, Everolimus. RAD001 can be purchased easily from RAD001 supplier. According to the RAD001 structure it contains 40-O-(2-hydroxyethyl) but it is a derivative of this compound in order to enhance its pharmacokinetics. For appropriate inhibition of mTOR pathway RAD IC50 is about 1nM. The RAD001 solubility can be gained in ethnol and water as well where as a 100mg/ml solution can be gained in DMSO. If someone wants to purchase RAD001 on can pay RAD001 price of 50$ and get a vial of 5mg. One main property of this compound is its action on mTOR1 pathway rather than mTOR2 pathway as it does not affect. [Read the Full Post]

GEFITINIB; AN EGFR INHIBITOR

3918 views | May 28 2012

PROPERTIES AND MODE OF ACTION Gefitinib is one of several tyrosine kinase inhibitors that are quite efficient in their activity. Gefitinib is actually an EGFR inhibitor. It is marketed by the two companies i.e., Teva and AstraZeneca. Gefitinib EGFR inhibitor is a strong inhibitory compound and Gefitinib structure shows the presence of a ring in it i.e., anilinoquinazoline. One can buy Gefitinib in the form of a 1 gm vial in approximately $80. Scientists can purchase Gefitinib for research or treatment purposes. Gefitinib solubility can be achieved in organic solvents like ethanol, DMSO and DMF and Gefitinib stability for approximately 2 years can be achieved if it is stored at -20 oC. Gefitinib IC50 for EGFR inhibition against Tyr 992 and Tyr 1173 is 37 nM and 57 nM respectively. Different types of assays have been designed to clinically analyze the pharmacokinetics and sensitivity of the drug. These assays are based upon some predicting markers e.g., EGFR mutated genes, copy number or K-Ras mutations. [Read the Full Post]

TEMSIROLIMUS

2139 views | May 27 2012

TEMSIROLIMUS: mTOR INHIBITOR mTOR protein kinase enzymes are the proteins that belongs to PI3-K (phosphatidylinositol 3-kinase) which is associated with the family of kinase proteins and are responsible for regulation of cell survival, growth, proliferation, transcriptional activities, cell migration and protein synthesis. Just because of the effect of these inhibitors on the above mentioned phenomenon, the targeting of these enzymes to treat various types of cancers is now an attractive approach. In past Rapamycin was known to be the most valuable inhibiting drug that belongs to the class of mTOR inhibitors but now days another member of this family named Temsirolimus mTOR inhibitor is more famous than that one. [Read the Full Post]