Blog of Signaling Pathways

Everolimus, as a mTOR inhibitor

7273 views | Sep 26 2012

EVEROLIMUS Everolimus, also known as RAD001 or SDZ RAD, is a orally active rapamycin analog with potent immunosuppressive activity. Similar with rapamycin, Everolimus is also identified as a potent inhibitor against mammalian target of rapamycin (mTOR). The preclinical trials in vitro and in vivo indicate that Everolimus as an immunosuppressant efficiently inhibits antigen-driven proliferation of human T-cell clones and prevents graft rejection in rat models of allotransplantation. In addition, Everolimus as an mTOR inhibitor also shows potential anti-tumor activity for treatment of multiple cancers. [Read the Full Post]

PARP INHIBITOR: STROKE ISCHEMIA AND CANCER

4235 views | Sep 27 2012

DEREGULATION OF PARP CASCADE: In humans, Poly (ADP-ribose) polymerase or PARP enzymes are encoded by PARP gene and regulate some crucial processes in the cells for example programmed cell death or the DNA repair system. They play their role in DNA repair process by repairing the ssDNA or single stranded DNA breaks on DNA. The interaction of BRCA1 and BRCA2 with them is very well documented which links the deregulation of PARP with ovarian and breast cancer because many of these types of cancers are associated with the mutations in BRCA1 and BRCA2 genes. For this reason, the inhibition of PARP is found to be an attractive therapeutic approach due to the specificity and effectiveness of PARP specific inhibitors against the cancers caused by BRCA genes. An inhibitor having specificity for PARP exhibits good results due to high sensitivity of cancer cells against PARP inhibiting drugs leaving the healthy cells unaffected. Hence the PARP inhibition mechanism has made them an attractive and better choice as compared to the conventional therapies affecting all the healthy cells as well. [Read the Full Post]

COMPOUND LIBRARIES AND THEIR USAGE

3552 views | Sep 25 2012

COMPOUND LIBRARY: A compound library is like a library of books where different titles and different content is available at a single place. Storage of compounds and their related data makes a compound library where different compounds are collected and arranged for some specific purposes. The compound screening of the library are placed, maintained and stored in a very scientific way. Drug discovery is one of the major purposes of making compound libraries. Recent technologies to organize and design chemical compound library have made the process of drug discovery a more interesting and attractive research area for the scientists and remarkable successes have been seen after the fast growing technologies have made its research easier. The most important thing after construction of compound library is its screening that is looking for the best suited compound relevant to question we are seeking the answer for and the compound that is biologically more active. [Read the Full Post]

KINASES INHIBITION FOR CANCER THERAPY

3402 views | Sep 24 2012

SIGNALING THROUGH KINASES: Kinase enzymes are the protein phosphorylating enzymes which act as gateways for the transmission of metabolic signals from the extracellular to intracellular environment of the cell. Kinases stimulate the cells to perform the processes which are necessary for the cell survival, proliferation and cell growth etc. Many types of kinase enzymes exist in the cells like serine/threonine kinases, receptor tyrosine kinases and non-receptor tyrosine kinases, Histidine kinases and the mixed kinases. Basic mechanism of action of kinase proteins is to aquire activated state by some sort of signaling compound that can be a special ligand or some other kind of kinase and send the stimulus to the subsequent molecule in form of its dephosphorylation or phosphorylation. One of the important examples of such kinases is p38 MAP kinase. [Read the Full Post]

BEZ235 as a dual PI3K/mTOR inhibitor

2938 views | Sep 23 2012

Characterization of BEZ235 The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway involves in various cellular processes including cell growth, proliferation, survival, and metabolism. is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. BEZ235, also known as NVP-BEZ235, is a potent and highly specific oral dual mTOR/PI3K inhibitor. BEZ235 structure reveals that it is an imidazoquinoline derivative, and is shown to be toxic to Waldenström's macroglobulinemia cells. BEZ235 has the solubility around 7 mg/mL in dimethyl sulfoxide (DMSO) however it is scarcely soluble in water and ethanol. And the approximate price of BEZ235 is $170 per 100 mg and BEZ235 price may vary according to the proportion purity of the preparation and/or from one BEZ235 supplier to different ones . [Read the Full Post]

PERIFOSINE, A NOVEL AKT INHIBITOR

3745 views | Sep 20 2012

PERIFOSINE Perifosine, also called D-21266 or KRX-0401, is identified as a heterocyclic alkylphospholipid and a drug candidate being developed for a variety of cancers. Perifosine is an orally active ark inhibitor which is completely bioavailable with antitumor capacities. Perifosine has displayed significant anti-proliferative and pro-apoptosis activity in vitro in vitro and in vivo, and now is currently being tested in different clinical trials. [Read the Full Post]

HIGH THROUGHPUT SCREENING AND DRUG DISCOVERIES

0 views | Sep 19 2012

INTRODUCTION: Various techniques are important in pharmaceutical industries which are used for the discovery of novel drugs, one of the most effective technique in this field is high throughput screening. This is also known as high throughput assay or HTS assays which are utilized for the assessment of pharmacological, biological or biochemical activities of a huge number of drugs by the aid of latest and automatic technology. This technique is not only useful for the discovery of appropriate ligands for ion channels, receptors, enzymes and other important pharmaceutical targets but also used for extensive studies of biochemical or desired cellular pathways by the help of novel and unknown chemical molecules. In this regard an example is of screening of kinase inhibitor library which is quiet easier than many traditional methodologies. High throughput screening reviews are an efficient source of understanding the importance of HTS screening, these reviews describe the accuracy and speed of the HTS screening in pharmaceutical industries in terms of business improvement structures and scientific approaches. [Read the Full Post]

BCL-2 INHIBITORS HARMONIZING APOPTOSIS

3078 views | Sep 18 2012

IMPROPER REGULATION OF BCL-2 PATHWAY IN TUMORS: Bcl-2 protein is abbreviated on basis of chromosomal translocations for the B-cell lymphoma 2 is a major apoptosis regulatory protein and is seen to be associated with it in the follicular lymphoma. Bcl-2 protein along with its other family members keeps a tight check on balancing the cell growth and apoptosis of the cells by keeping an interaction with each other. Any disturbance in the homeostatic balance between apoptosis and growth of cells usually results in the aberrations associated with various types of cancers. Hence using the Bcl-2 inhibitors to achieve Bcl-2 inhibition seems to be an attractive and promising strategy for the treatment of many types of cancers. Different Bcl-2 antagonists are designed on the basis of this strategy among them some are showing promising results at the pre-clinical and clinical levels. As the decrease in apoptosis is a key feature of the development of some sort of cancer, so it was not very surprising to find an association between the Bcl-2 gene, breast cancer, melanoma, prostate cancer and lung carcinomas along with the neurodegenerative problems like autoimmune disorders and schizophrenia. [Read the Full Post]

INHIBITION OF mTOR FOR CANCER THERAPEUTICS

2899 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]

CANCER AND CDK INHIBITION

3443 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

8031 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]

EGFR INHIBITORS AGAINST THE CANCERS

4820 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]

PAZOPANIB: LATEST VEGFR INHIBITOR

3684 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]

VORINOSTAT: A HYDROXAMIC ACID

5001 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]

PARP INHIBITOR: TREATMENT OF STROK, ISCHEMIA AND CANCER

3607 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]

LENALIDOMIDE – AN ANTI-INFLAMMATORY DRUG

3998 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]

EVEROLIMUS- mTOR PATHWAY INHIBITOR

3729 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]

ERLOTINIB– INHIBITOR OF EGFR

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]

HISTONE DEACETYLASE INHIBITORS BEYOND CANCER TREATMENT

4581 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]