Blog of Signaling Pathways

DASATINIB; An inhibitor of Receptor Tyrosine Kinase

11948 views | Jul 04 2012

CHARACTERISTICS OF DASATINIB The amplified death rate because of cancer and multidrug resistance development in cancer cells for existing drugs are the persuasive force for the researchers as well as scientists to explore new drugs that have better efficiency. Each cellular system is organized by a diversity of controllers called cell cycle regulatory proteins.Cancer cells have the capability to mutate themselves in a variety of ways which make them to detour the action of a specific drug. Another concern with the cancer is that it metastasizes. Other difficulty with the chemotherapy of cancerous cells is toxicity. So considering afore mentioned problems it is evident and compulsory to search for new drugs. Due to above mentioned problematic effects of Imatinib which has been administered for years induces scientists to search for a more mild and more active drug. In this matter a new drug called Dasatinib was discovered by Jagabandhu Das. In contrast to Imatinib, Dasatinib BMS 354825 became renowned due to its lesser harmful and more efficient nature. This drug was discovered by Squibb Company and it is sold as Sprycel. [Read the Full Post]

TEMSIROLIMUS

3700 views | Jul 03 2012

TEMSIROLIMUS: mTOR INHIBITOR mTOR belongs to phosphatidylinositol 3-kinase family which are the protein kinases that regulate cell survival, growth, proliferation, transcriptional activities, cell migration and protein synthesis. Due to the involvement of these in above mentioned processes they have gained importance from therapy point of view in cancer treatment. In comparison to Rapamycin Temsirolimus mTOR inhibitor gained importance for the past few years. [Read the Full Post]

TEMSIROLIMUS

2818 views | Jul 02 2012

TEMSIROLIMUS ASmTOR INHIBITOR mTOR belongs to phosphatidylinositol 3-kinasefamily which are the protein kinases that regulate cell survival, growth, proliferation, transcriptional activities, cell migration and protein synthesis. Due to the involvement of these in above mentioned processes they have gained importance from therapy point of view in cancer treatment. In cosmparison to RapamycinTemsirolimus mTOR inhibitor gained importance for the past few years. [Read the Full Post]

BORTEZOMIB: AN ANTI-PROTEASOMAL AGENT

4089 views | Jul 01 2012

BORTEZOMIB: INTRODUCTION In cell among the tiny organelles proteasomes are the foremost vital ones. They play necessary role in the correct regulation of the cell cycle by removing the proteins that don't seem to be necessary for cell. In cancer cell it rarely happens that the proteins which are involved in the controlling the dysregulated growth of the cells are excised by proteasomes. A promising target for the therapy of cancer is to inhibit proteasomes so that the uncontrolled growth is inhibited. A variety of compounds were typically used for cancer therapy that inhibits proteasomes. Among them EGCG additionally referred to as Epigallocatechin-3-gallate, Disulfiram and Salinosporamide-A that are present in green tea were used. The primary inhibitor of proteasomes that got approved to enter clinical trials for cancer therapy is Bortezomib. [Read the Full Post]

NILOTINIB

6704 views | Jun 28 2012

CHRONIC MYELOGENOUS LEUKEMIA AND PHILADELPHIA CHROMOSOME During meiosis if BCR and tyrosine kinase ABL are unable to separate and fuse together it leads to condition called Philadelphia chromosome. Due to the fusion of these genes it leads to translation of abnormal protein which acts as malfunctioned tyrosine kinase that makes it oncoprotein. Around 90% of patients suffering from Ph+ also suffer from chronic myelogenous leukemia or CML. This fusion protein is being targeted for therapy of cancer since it is involved in CML and various researches are being carried out in this regard. An inhibitor of this protein is Nilotinib bcr-abl inhibitor which is used to treat CML. [Read the Full Post]

EVEROLIMUS-AN INHIBITOR OF mTOR PATHWAY

3064 views | Jun 29 2012

EVEROLIMUS: INTRODUCTION mTOR pathway is among the different vital regulators of cell cycle which are involved in its regulatory activities likecell proliferation, growth, migration and activities related to transcription and translation. mTOR is the translational product of FRAP1 gene which phosphorylates threonine/serine residues in protein. Defected or dysregulated mTOR pathway is a common reason of developing cancerous cells. Therefore, these proteins are also targeted while looking for an effective anti-cancer therapy. Everolimus mTOR inhibitor is among the efficientinhibitors that have been searched so far. Afinitor Everolimus is the brand name of inhibitor and developed by Novartis. Everolimus structure contains 40-O-(2-hydroxyethyl) derivative and properties related to ispharmacokinetics are found to be improved by the presence of oxygen at position 40. Everolimus IC50 for mTOR is around 1nM. Everolimus solubility is 100mg per ml of DMSO while it is also soluble in ethanol and water. It is administered orally and Everolimus price $60 in packaging of 5mg.It is distributed in dry ice. [Read the Full Post]

SORAFENIB- A MULTIKINASE TYROSINE INHIBITOR

3597 views | Jun 27 2012

SORAFENIB: INTRODUCTION Various kinds of non-receptor tyrosine kinases or receptor tyrosine kinases (RTKs) are available in the cells which are employed in responding to intra or extracellular stimulusby carrying out either initiatory or inhibitory action on various signaling pathways. Any sort of problem in this process may cause cancer. Inhibition of kinase enzymes to prevent some mal-expressed or over-expressed gene causing cancer is found to be an effective tool. Inhibition of various kinases is being done by using single inhibitor. Since malfunctioned tyrosine kinases are involved in onset of cancer, research is being done on their inhibitors for cancer therapy.Many of them are giving promising results in their clinical trials.An important example of these inhibiting drugs is Sorafenib VEGFR inhibitor that has been found to inhibit the protein kinases except respective VEGFR. When SorafenibRaf inhibitor was given Raf/MEK/ERK pathway was found inhibited. [Read the Full Post]

HISTONE DEACETYLASE INHIBITORS – CANCERS AND BEYOND

4711 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

4227 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

4604 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

5190 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

5715 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

3131 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

3478 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

3044 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+

6512 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

3664 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

3510 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

3938 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

3138 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]