Blog of Signaling Pathways

DASATINIB; An Inhibitor of Receptor Tyrosine Kinase

0 views | Sep 06 2012

CHARACTERISTICS OF DASATINIB Experts and also scientists are trying hard to find improve drug that will be able to possess efficiency as against cancer which has become responsible of heavy death all over the world and also resistance towards the available drugs in cancer cells is also motivating scientists. Cancer cells avoid both the action of particular medicine by mutating themselves in a number of steps. Metastasis is actually also other problem related to disease. For chemotherapy of disease cell toxicity increases the problem. To attack these afore mentioned errors the only key to combat it to be able to devise new medication. Imatinib was used for many years but toxicity and other consequences mentioned above it obligate scientists to develop one less harmful and more efficient prescription. So in this respect Jagabandhu Das developed one medicine known as Dasatinib. Dasatinib BMS 354825 got very popular compared to Imatinib because of its less toxicity and more performance. It's developed through a pharmaceutical business Squibb and offered under the trade name on Sprycel. [Read the Full Post]


3648 views | Sep 05 2012

LENALIDOMIDE: INTRODUCTION Tumor Necrosis factor (TNF) is a pro-inflammatory cytokine, the high levels of which signify inflammation in several disease conditions like autoimmune disorders (e.g. - rheumatoid arthritis, Crohn's disease and ankylosing spondylitis etc.), numerous cancers, skin diseases like psoriasis and refractory asthma. This is often the rationale that TNF-alpha inhibitors are given such importance in medical literature. Starting from natural compounds like curcumin, cannabis and green tea to xanthine derivatives, hallucination inducing compounds and also the best of all monoclonal antibodies, several TNF inhibitors are being studied in several and physiological conditions.As a result of its significance, TNF-alpha inhibition in cancers researchers got abundant attention. [Read the Full Post]


3366 views | Sep 04 2012

EVEROLIMUS Regulatory activities of the cell that are associated with its multiplication, movement, transcription and additionally in translation of the genes is controlled by mTOR pathway that is among the necessary numerous cell cycle regulators. FRAP1 gene is translated to provide mTOR that phosphorylates serine/threonine residue of proteins. Cancer typically arises from the down-regulation of this mTOR cascade. Therefore for targeted cancer therapy proteins like are also taken into consideration. Different types of inhibitors are being searched and Everolimus mTOR inhibitor is amongst the very promising inhibitors. Novartis that is pharmaceutical company created it and sell it with as Afinitor Everolimus that is its trade name. Since structural studies revealed that Everolimus may be a derivative of 40-O-(2-hydroxyethyl), the pharmacokinetic properties are appeared to be improved owing to the availability of oxygen atom the 40 position. Against mTOR Everolimus IC50 is approximately 1nM. Around 100mg/ml of DMSO is appropriate for Everolimus solubility. It is water and ethanol soluble. The mode of administration of Everolimus is via 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]


517 views | Sep 03 2012

CHARACTERISTICS OF ERLOTINIB Erlotinib is one of the tyrosine kinase inhibitors which is also referred OSI-420 EGFR inhibitor which is typically named as HCl salt. Epidermal growth factor tyrosine kinase receptor is sometimes seen abnormal in numerous kinds of cancers so that they are being utilized for the anti-cancer therapy. Plenty of new medicines are being created by using a similar approach [1]. Erlotinib structure revealed that it contained 2 quinazoline rings in its structures and it showed to inhibit the EGFR auto phosphorylation which eventually stops the pathway that 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 readily oxidized therefore care should be taken to extend its shelf life. Approximately $65 per 1000mg is Erlotinib price and any one can get OSI-420 for any kind of purpose under this trade name. [Read the Full Post]


4052 views | Sep 02 2012

EPIGENEITIC MODULATION AND HDAC INHIBITORS In cellular genome a major part comprises of histone proteins and these proteins upon addition of acetyle group perform some of the most important cellular pathways are controlled by these proteins, these pathways include cell growth and proliferation and programmed cell death. When the acetyle group is detached from histones the process of apoptosis starts because most of the genetic expression of some vital proteins is ceased due to deacetylation and in addition to this the DNA condensation is also increased due to increased DNA binding capacity. It has been noticed that during neurodegenerative diseases the process of deacetylation is disturbed which leads to different types of cancers and tumors which is characterized by uncontrolled cell proliferation. These studies encouraged the discoveries of HDAC inhibitors and also enlighten the HDAC inhibition process. In preclinical and clinical evaluations HDAC inhibitions have been applied which leads to the successful and detailed use of this process by good number of researchers. Various activity assays are available for the estimation of HDACs levels. Kits are available for such assays however these can also be performed manually in the lab. HDAC inhibitors analysis can also be done by a nonisotopic assay which is microplate reader compatible and test for robotic screening and compound profiling is also available or another assay which is suitable for high throughput screening. [Read the Full Post]


3705 views | Aug 27 2012

SIGNALING CASCADE AND DEVELOPMENT OF CANCER: Insulin like growth factor 1 is one of the signaling molecules in the human cells abbreviated as IGF-I also known as somatomedin or sulfation factor. As the name indicates, the structure of the protein resembles insulin and is responsible for stimulating a signaling cascade via a transmembrane receptor protein i.e., IGF-1 receptor. This receptor is very important due to its role in the process of insulin signaling and aging. This preceptor has also been connected with different types of cancers e.g., prostate cancer, breast cancer and lung cancer. This receptor has been found to provide resistance to the cells against radiotherapy and chemotherapy and hence shows anti-apoptotic characteristics. One example of such resistance is that of Erlotinib, EGFR inhibitors which is used against breast cancer and inhibits EGFR signaling pathway but IGF1-R in these cells produces resistance against the drug. It has been reported to form heterodimers that tend the EGFR pathway to continue rather than inhibiting it. This relationship between IGF-R and EGFR has been studied in breast cancer and the development of metastasis or tumor invasion by angiogenesis was reported. Therefore, inhibiting IGF1-R can be a way to prevent lots of signaling cascades towards malignancies. [Read the Full Post]


3514 views | Aug 26 2012

c-MET INHIBITION: APPLICATIONS IN CANCERS: A proto-oncogene encoding the hepatocyte growth factor receptor or HGF-R is known as c-Met, and its hyperactivation causes certain changes like angiogenesis or formation of the new blood vessels leading to the invasive growth of tumor. The aberrant regulation of Met has reported to the leading cause of many types of cancer like liver cancer, stomach cancer, breast cancer, ovarian cancer, thyroid cancer and brain cancers. Due to this particular property of c-Met gene, its inhibition process has become an attractive target for the therapeutic use. That’s why huge research is being made for the synthesis of antagonist of c-Met or simply am7 inhibitor having clinical and therapeutic implications. Along with this application, the c-Met agonists and antagonists are being utilized for understanding of different cellular cascades and throwing light on interactions of c-Met with other molecules. Many of these commercial c-Met inhibitors like bayer kinase inhibitors are easily available from their suppliers and one has an easy access to them. [Read the Full Post]


4651 views | Aug 24 2012

PATHWAY OF HSP90 AND CANCER CELL LINES: Heat shock protein 90 or Hsp90 is actually a non-fibrous protein which gained its name from its molecular weight that is 90kDa. Hsp90 is most abundant cytoplasmic protein which plays a significant role in cells by acting like a molecular chaperone for many proteins related to some important signaling cascades of the cell. Different proteins chaperones that are existing in the cell, involve serine/theronine kinases and tyrosine kinases as well hence they are very much important for the proper regulation of cell growth and cell cycle. A detailed research is carried out to describe the relation between Hsp90 and cancers. To inhibit this chaperone i.e. Hsp90, the simple strategy of designing Hsp protein inhibitor was developed when Hsp90 was found to be existing in different cancerous cell lines activated through the activation of oncogenes. It has been proved a very fruitful therapy for cancer. [Read the Full Post]


3033 views | Aug 23 2012

KINASE-DOWNSTREAM SIGNALING: Kinases act as windows for cells to the outer world, these enzymes are triggered by the signals coming from other cells, stimuli from the environment and as a result these kinases carry out phosphorylaiton of various molecules to transmit downstream signals. There are many types of kinase enzymes such as pim kinase and out of these most common are protein kinases. These protein kinases can also be further subdivided into various categories like receptor tyrosine kinase enzyme, threonine/serine protein kinases, mixed kinases and histidine protein kinases. Many of the kinase agonists and kinase antagonists have been employed for the understanding of multiple cellular pathways during research under physiological environment. Reviews on kinase inhibitors can prove the importance of these small compounds. There are various kinase assays are available which can be used for the activity assessment of a kinase enzyme in a given state. [Read the Full Post]


4293 views | Aug 22 2012

HDAC INHIBITION: A SOURCE OF EPIGENETIC MODULATION Histone acetylation is an essential process in functions like cell growth and cellular death by causing the inhibition of transcription of proteins caused by removal of the acetyl groups from the histone proteins, as a result of which the binding of DNA is increased, causing it to be condensed. A disturbance in this phenomenon leads to an uncontrolled growth of the cells that leads to the production of tumors and neurodegenerative diseases as well. HDAC inhibition is performed to treat various forms of tumors by using HDAC-2 inhibitors. Different successful studies at various levels have elucidated the mechanism of action of HDAC inhibitors leading to their enormous applications in various preclinical and clinical trials. The levels of HDAC inhibitors can be assessed by the use of different sort of assays specially developed for this reason. These chemical assays can be performed in laboratory by using various kits. The researchers can perform nonisotopic HDAC inhibitor and microplate reader compatible assay and the one for the robotic screening and compound profiling. In addition to it a simple flourogenic assay can also be used for the high-throughput screening process. [Read the Full Post]


3169 views | Aug 21 2012

THE BASIC CONCEPT OF COMPOUND LIBRARY: The collection of data about different compounds at a place where all these compounds can be analyzed by the good worth of their storage is known as a compound library. Hence compound library is basically a collection or arrangement of different compounds. The maintenance, storage and placing of these screening compounds is actually a proper scientific way. The development of different new and emerging technologies in designing and managing of a chemical screening library has brought very remarkable success and changes in the procedure of drug discovery and these new changes have a great and positive impact on the ongoing research on drug discovery [1]. The most determining and crucial step in this procedure of compound library screening is the selection of biologically relevant and useful compounds and molecules that is usually guided by some experts of this area who would must devise some detailed protocols and schemes to make this process of selection faster, more efficient and better than ever in generating a resourceful research chemicals library. State-of-the-art methodologies that include both the fragment-based library designing and the structure-based small molecule library designing procedure is supported by the latest and efficient software tools which ensure a promising implementation of a small molecule drug screening library. [Read the Full Post]


4708 views | Aug 20 2012

c-MET AND ITS INHIBITION: c-Met is encoded by a proto-oncogene and is also known as HGF-R or hepatocyte growth factor receptor. As it is a proto-oncogene, therefore, its hyperactivation is involved in development of different cancers. c-Met is known to form new blood vessels in growing tumors and hence help their invasion to other tissues. Different examples of cancers involving c-Met aberrant behavior are stomach cancer, liver cancer, breast cancer, thyroid cancer, ovarian cancer and brain cancer. Because of involvement of this particular oncoprotein in many cancers, it has remained target in lots of research related to anti-cancer therapy. Lots of c-Met antagonists have been developed and one of the examples is c-Met inhibitors that has been implicated clinically and therapeutically. Different other antagonists and agonists of c-Met are also being used in order to get an understanding about different functions of c-Met and the types of interactions that it has with other molecules in the signaling cascade. Many of the c-Met inhibitors are commercially available at reasonable prices for example tyrosine kinase inhibitor. These inhibitors can be easily bought from the suppliers for any purpose. [Read the Full Post]


3933 views | Aug 19 2012

COMPOUND LIBRARIES: INTRODUCTION AND FUNCTIONS A fair to a big group of the stored compounds which can be used for industrial manufacturing of drugs or the high-throughput screening assay based drug discovery, is defined as a compound library. This collection or group of compounds is supported by the specific kind of database that contains the relevant information and knowledge about the included compounds and that information includes the compound’s purity, preparation, chemical structure, chemical, physical and pharmacological properties [1]. A lot of compound libraries are commercially available and they might contain a mixture of some common or some unique biochemical compounds. A detailed file containing the complete information regarding the compounds is presented in the research chemical library and this file is purchasable from the relevant suppliers. These compound libraries are most advantageous in the high throughput screening assays in which the target of a drug is screened against a number of different compounds that are taking space in the library. More the number of compounds in a compound library more are the chances of getting a ‘hit’ in screening compound procedure. [Read the Full Post]


4740 views | Aug 17 2012

EGFR AND DEVELOPMENT OF CANCER: Among a variety of signal transduction pathways vital for cell survival, growth, and proliferation etc. EGFR pathway is considered to be quite important. Its importance has been judged by analyzing the processes like tumor development and some other diseases occurring due to uncontrolled growth of cells. Mostly EGFR signaling pathway malfunctioning has been linked with the development of such types of diseases in the body for example; colon cancer, breast and lung cancer and with anal cancer, multiform Glioblastoma and epithelial cancer. Therefore targeting EGFR for cancer therapy is a feasible approach. This EGFR inhibiting strategy magnifies the HER-1inhibitor and its importance. These inhibitors have a very significant role in the patients’ survival from the disease. Different EGFR agonists and antagonists are used for the purpose of unveiling the role of this molecule in the cell as well as looking for a most efficient EGFR inhibitor. These inhibitors are available at a very reasonable price and can be bought for any purpose. [Read the Full Post]


4902 views | Aug 16 2012

HSP90 CASCADE AND CANCER CELLS: Hsp90 or the Heat shock protein 90 is a non fibrous protein that gained its name on the basis of its molecular weight i.e., 90kDa. Heat shock protein 90 is the most abundant protein present in cytoplasm that plays a significant role in the cells by acting as molecular chaperones for different proteins associated with some important signaling pathways in the cells. Various molecular chaperones existing in the cells, involves in the tyrosine kinases and serine/theronine kinases as well, so they are very important for proper regulation of cell cycle and cell growth. A complete research has been done to describe the relation between cancer and Hsp90. For the inhibition of Hsp90 chaperone a simple strategy is designed i.e., development of Hsp-60 inhibitor in case of presence of Hsp90 in the cancerous cells and activated by the activation of various oncogenes. It was proved to be an efficient therapy for the treatment of cancer. [Read the Full Post]


4052 views | Aug 15 2012

HDAC INHIBITION AND EPIGENETIC MODULATION An important process; histone acetylation is related to cellular functions for example cell death and cell growth stimulating the protein transcription inhibition by removing the acetyl groups from the related proteins hence causing the increase in DNA binding and making it more condensed. Any disturbance in this process leads to the uncontrolled cellular growth that further leads to the tumor production and also the neurodegenerative diseases. Histone deacetylase inhibition is carried out for the treatment of different types of tumors by using the HDAC-6 inhibitors. Various successful studies at different levels have exhibited the mode of action of histone deacetylase inhibitors further leading to their vast area of applications in different clinical and pre-clinical studies. The HDAC inhibitors levels can be analyzed by using various types of assays specifically developed for this purpose. These assays can be carried out in the labs through different kits. Researchers can perform microplate reader compatible assay and the nonisotopic HDAC inhibitor assay and also the one for compound profiling and robotic screening. In addition to this simple flourogenic assay may also be carried out for the process of high-throughput screening. [Read the Full Post]


2500 views | Aug 13 2012

SIGNALLING OF MEK PATHWAY: Various types of cells exist on the surface of the cells helping the cells to coordinate with the environment and the other cells. The growth factor receptors are such receptors which after getting triggered by the ligands usually play a very vital role in the process of cell signaling hence stimulate different pathways that are necessary for the cell survival and growth. One such example is MEK kinase cascade that plays an important role in pro-survival signaling. The inhibition of MEK kinase pathway is one of the attractive strategies when there is a need to inhibit un-necessary proliferation of cells in case of cancer. It has been studied that MEK signaling pathway gets hyperactivated in the cancer cells, so scientists devised a good therapeutic tool against cancer by designing different inhibitors of MEK pathway. 20 years ago, the structural properties of MEK molecule were described [1], which make the approach of scientists much easier for specific MAP2k2 inhibitor. [Read the Full Post]


2467 views | Aug 14 2012

SIGNALLING VIA mTOR: mTOR is serine/threonine kinase protein and stands for “mammalian target of Rapamycin”. It also known as FRAP1 i.e., FK506-binding protein 12 - rapamycin associated protein-1. It as encoded by a gene known as FRAP1.mTOR is known to be involved in controlling various cellular processes for example; cell growth, survival, proliferation, transcriptional regulation and migration of proteins. mTOR regulatory proteins function in these processes by responding to the energy and nutrient status of the cell. As mTOR is involved in lots of cellular processes regarding its growth proliferation and survival, it can provide a target in cancer therapy; therefore, mTORc1 inhibitors have been designed that can control the cancer progression and development by inhibiting the functions mTOR performs. Inhibiting mTOR signaling pathway thus controls the tumor growth and limits tumorigenesis. [Read the Full Post]


4111 views | Aug 12 2012

SIGNALING PATHWAY AND CANCER: One of the important signaling molecules in body of human cells is the Insulin like growth factor 1 and abbreviated as IGF-I and also known as sulfation factor or somatomedin. Structure of this protein, as indicated by the name, resembles insulin and responsible of stimulating a signaling pathway through transmembrane receptor protein i.e., receptor IGF-1. The receptor is very much important for its role in process of aging and signaling of insulin. IGF-1 receptor is also connected to different types of tumors like breast cancer, lung cancer and prostate cancer. It was observed that this receptor offers resistance against chemotherapy and radiotherapy in the cells hence showing the anti-apoptotic activity. An important example of such resistance is Erlotinib, HER-1 inhibitors that is used against breast cancer and causes inhibition of EGFR signaling pathway but IGF1 receptor in cells generates resistance against this drug. The formation of hetrodimers has been reported that stimulate the EGFR cascade to further continue rather than its inhibition. [Read the Full Post]


3719 views | Aug 10 2012

CELL PROLIFERATION AND AKT PATHWAY Signal transduction pathways involve various types of kinase enzymes. AKT kinase is such an enzyme that is responsible of phosphorylating the proteins on their specifically serine/threonine sites specifically. It is also named as PKB which means Protein kinase B. It is involved in different kinds of cellular processes like apoptosis, transcription, translation, metabolism and the most important of above all is the cell proliferation and cell migration. Many cancerous cells have been found to exhibit AKT dysfunction therefore it is thought to have an important role in the regulation of cell cycle. AKT pathway gets active by stimulation from PI3K and it also activates by itself mTOR protein to initiate the further process. When PI3K gets hyperactivated, there is an increase in rate of cell division process etc. hence caused tumorigenesis. As compared to any other pathway of signal transduction, this AKT pathway exists more frequently in the cancer cells due to event of amplification, mutation and translocation in its kinase proteins. To fight against various types of cancers and tumors the strategy applied is to target any one of these kinase proteins of this pathway and the AKT inhibitors were found quite good to be used for the treatment of cancer. [Read the Full Post]