Blog of Signaling Pathways


2573 views | Sep 17 2012

SIGNALLING BY mTOR: A serine/threonine kinase protein named as mTOR stands for the “mammalian target of Rapamycin”. It is also known as FRAP1 that is a FK506-binding protein 12 - rapamycin associated protein-1. FRAP1 is the gene that is responsible of encoding this protein. mTOR protein is involved in many processes in the cell like cell survival, cell growth and proliferation, migration of proteins and the transcriptional regulation of cell. The mTOR regulatory proteins regulate these processes in response to the nutrient and energy status of the cell. mTOR can be an attractive target for the cancer therapy due to its active role in the different cellular processes like growth, proliferation and survival of the cell. Hence some specific mtorc2 inhibitors are synthesized that have the capability of controlling the cancer development and progression by inhibiting the functions performed by mTOR proteins. So by inhibiting the mTOR signaling pathway we can control the growth of tumor and check the tumorigenesis. [Read the Full Post]


3017 views | Sep 16 2012

CDK/CYCLIN DEPENDENT KINASES: Among a large number of cell cycle regulators, cyclin dependent kinases also known as CDKs are known to be very important ones. These kinases play a crucial role in the processes of transcription, mRNA processing and cellular differentiation. These kinases have a small structure with an important kinase domain and depend on another small protein for proper activity i.e., cyclin. As these are very important kinases in cell cycle, they can be targeted in order to prevent proliferation of cancer cells. Inhibition of these kinases has shown induction of apoptosis especially in cancer cells. Various inhibitors have been designed against different kinases to fight cancer and inflammation, preserved in kinase inhibitor library for screening amongst these CDK2 inhibitors have been found to be most effective. Inhibiting cell cycle regulators may have some hazards as well; therefore inhibitors should be developed carefully in order to avoid these side effects. [Read the Full Post]

BEZ235-dual PI3K/mTOR inhibitor

7306 views | Sep 15 2012

BEZ235 (NVP-BEZ235) BEZ235 is a novel orally-bioavailable PI3-kinase inhibitor, and shows strong antiproliferative and apoptotic activity in breast cancer, prostate cancer, and myeloma cell lines. In vivo study indicates that BEZ235 produces antitumor activity in xenograft models harboring PI3K pathway alterations. In preclinical toxicology studies, BEZ235 treatment is well tolerated. [Read the Full Post]


4316 views | Sep 12 2012

INHIBITION OF EGFR: Among those few cascades which play an important role in the functioning of cells, epidermal growth factor receptor or EGFR pathway is one that has a vital role in growth, survival and proliferation of cells. The importance of this cascade can only be observed and understood in case of development of tumors and fatal diseases related to the uncontrolled cell growth caused by the improper regulation of EGFR signaling pathway. Over or mutated expression of the EGFR is associated with different types of cancers like colon, lung and breast cancers and with multiform glioblastoma, anal and epithelial cancers. Therefore the treatment of these cancers by using the phenomenon of EGFR inhibition is found to be an attractive approach that led to magnify the importance of Erbb1 inhibitor. These inhibitors along with their use in clinical processes, are also concerned with the survival of patients and different EGFR antagonists and agonists are also in use for the revelation of various other cascades and the effects of EGFR pathway on them. EGFR inhibitors can be obtained from any relevant supplier at a very normal cost. [Read the Full Post]


3249 views | Sep 11 2012

PAZOPANIB: A very famous pharmaceutical company named GlaxoSmithKline is the manufacturer of a very important anticancer drug Pazopanib Votrient also called Pazopanib VEGFR inhibitor and is selling it by the market name Votrient. Pazopanib is a quick source of anti-angiogenic activity that inhibits VEGF, R1, VEGFR2 and VEGFR3 in conjunction with the β subtypes and c-kit RTKs and PDGFR-a. Pazopanib is such a tiny structure that got fame only in previous years by showing its remarkable activity in various sorts of cancers. Pazopanib VEGFR-PDGFR inhibitor is indeed one amongst those necessary inhibitors that are currently approved for the utilization at clinical level [1]. Pazopanib structure reveals the presence of a sulfonamide group. One can purchase Pazopanib from supplier Pazopanib by paying Pazopanib price that is around $100 per a 25mg packing under the market name Votrient or GW786034. Its price might vary among the suppliers. Pazopanib solubility is ideally detected in DMSO however it is fully insoluble in water and ethanol. It is stability is increased for nearly 2 years if preserved at -20oC. The studies revealed that Pazopanib IC50 value for VEGF-R1 is 10nM, for VEGF-R2 is 30nM and for VEGF-R3 is 47 nM. Pazopanib IC50 values for few related kinases for example PDFGR-beta is 82 nM, c-fms is 146 nM, c-kit is 74 nM and FGFR1 is 140 nM. [Read the Full Post]


4222 views | Sep 10 2012

VORINOSTAT OR SAHA (SUBEROYLANILIDE HYDROXAMIC ACID): Histone deacetylase inhibitors or HDACi perform functions in the regulation of gene expression, cell cycle arrest, apoptosis stimulation in cancer cells and variation of different pathways in cancer cells such as cellular proliferation due to hyperacetylating the histone proteins. HDAC inhibitors are one of the leading approach for the treatment of cancers and tumors and among these inhibitors Vorinostat SAHA is the important one. This inhibitor is found to have strong anti-oncogenic properties and the Vorinostat structure contains a molecules having hydroxamic acid. For both classes of HDAC inhibitors that is class I and II the Vorinostat IC50 is about 50nM. The solubility of Vorinostat is around 2mg/ml in ethanol where it is highly soluble in DMSO in which 65mg/ml is Vorinostat solubility but it is poorly soluble in water. Stability of Vorinostat is of about 24 months when stored at -20 ºC. One can purchase Vorinostat for research purpose from any of the Vorinostat supplier by spending Vorinostat price that is $26 for a vial of 100mg however the prices are variably depending upon purity of the salt and supplier. Amongst different HDAC inhibitors the first FDA approved such inhibitor is Vorinostat HDAC inhibitor for the treatment of T-cell lymphoma. [Read the Full Post]


3127 views | Sep 09 2012

DEREGULATION OF PARP CASCADE AND ITS APPLICATIONS: Poly ADP-ribose polymerases or PARP are the translated product of PARP genes located in human genome. These proteins play some of the vital roles in the cell such as apoptosis and DNA repair mechanism. The repair mechanism of DNA is specific for the single stranded DNA (ss DNA) breaks. A reasonable work has been reported about the interaction of BRCA1 and BRCA2 and this knowledge leads to the understanding of PARP deregulation causes or links with ovarian and breast cancer as different research reports concluded the mutations of these two genes are present in these cancers. Due to these reasons the PARP inhibition mechanism has become an efficient therapeutic tool for cancer treatment [1]. The specific PARP inhibitors may have efficient results against tumors and cancers with BRCAness. The beauty of these PARP inhibitors is that the normal cells are not affected where tumors cells are only targeted. Mechanism of PARP inhibitor tells about the efficacy of these inhibitors in treatment of cancers and because of their efficient actions the old therapies are becoming less popular as they affect the normal cells as well. [Read the Full Post]

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]


3477 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]


3237 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]


3856 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]


3542 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]


3399 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]


4454 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]


2930 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]


4096 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]


3053 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]


4547 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]


3798 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]