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HIGH THROUGHPUT SCREENING HELPING THE DRUG DISCOVERY

3422 views | Oct 14 2012

HIGH THROUGHPUT SCREENING: INTRODUCTION: In pharmaceutical industries different techniques are important and used for the novel drug discovery. Among these techniques the most effective one in this area is high throughput chemical screening. It is also named as HTS assays or high throughput assays which are being used for the biological, pharmacological assessment or the assessment of biochemical activities of a large number of drugs by the help of the latest automatic technology. Such technology is not only helpful in discovery of appropriate receptors, enzymes, ligands for different ion channels and the other pharmacologically important targets but also used in the extensive studies of various desired biochemical or cellular pathways by the aid of unknown and novel chemical agents. Regarding this an important example is of the screening of kinase inhibitor library for screening that is much easier than various other traditional methodologies. Reviews of high throughput screening are an efficient source of acknowledging the importance of HTS. These reviews reveal the speed and accuracy of high throughput screening in the pharmaceutical industries in improving the scientific approaches and business structures. [Read the Full Post]

GDC-0941, A NOVEL PI3K INHIBITOR

9429 views | Oct 12 2012

GDC-0941 As is known, there have been several identified PI3 kinases, which are divided into classes IA, 1B, II, and III according to the differences of sequence homology and substrate preference. Besides, the PI3K superfamily also includes the Class IV PIK related enzyme family of protein kinases including mTOR, ATM, ATR, and DNA-PK. Of which, Class IA PI3K is a heterodimer composed of a p110 catalytic subunit and a p85 regulatory subunit, and there are three variants of the p110 catalytic subunit designated p110α, β, or δ catalytic subunit. PI3 Kinase is an oncogene that is commonly mutated in cancer. Hence inhibition of PI3K, and in particular p110α, is a promising target for cancer treatment. [Read the Full Post]

KINASE INHIBITORS IN CANCER THERAPY

3180 views | Oct 10 2012

KINASES IN CELL SIGNALLING: Kinases can rightly be called as the gateways of the cells due to their role in signal transduction in the cell. They function by activating or stimulating the critical pathway by phosphorylating the protein molecules. After getting stimulated enzymes allow the cells to perform some specific functions necessary for its proliferation, survival and growth etc. kinases are of many types which are Receptor tyrosine kinases (RTKs), non-receptor tyrosine kinases (NRTKs) and serine/threonine kinases. Mixed kinases and histidine kinases are also some of the examples of kinases. Basically kinases themselves get activated by a signaling molecule like a ligand from the extracellular environment or some other kinases and further activate subsequent molecule by phosphorylating or dephosphorylating them. Aurora kinase is an important example of kinase enzymes. Different types of agonist and antagonist molecules are used to study and unveil different functions of kinases in the cells. Kinase inhibitor is one of the examples of outcomes of such research on kinases and their inhibition. Different types of kinase assays are also there to study and analyze some specific kinds of kinases. [Read the Full Post]

MK-2206, as a pan Akt inhibitor

6928 views | Oct 09 2012

MK-2206 AKT/Protein Kinase B is a serine/threonine-specific protein kinase that constitutes an important pathway that regulates the signaling of multiple essential biological processes such as glucose metabolism, apoptosis, cell proliferation, and cell migration. AKT can be recruited to the membrane and activated with increases in PIP3 induced by PI3K. Since activating mutations of PI3K occur in human tumors, the AKT pathway is a promising potential target for cancer chemotherapy. MK-2206, is identified as an orally bioavailable allosteric inhibitor of Akt with potential antineoplastic activity. MK-2206 has shown cytotoxic activity in vitro cell line, such as T-cell acute lymphoblastic leukemia (T-ALL), and the efficacy of MK-2206 also has been proven in preclinical models of human cancers. [Read the Full Post]

Everolimus, as a derivative of rapamycin

3601 views | Oct 08 2012

CHARACTERIZATION OF EVEROLIMUS The PI3K/Akt/mTOR pathway plays a important role in various cellular processes including cell growth, proliferation, survival, and metabolism. is found to be constitutively activated in multiple tumor cells, providing potential targets for anticancer therapy. Everolimus, also known as RAD001, is a potent and highly specific mTOR inhibitor. Everolimus, together with Temsirolimus, are both important derivatives of Rapamycin. Everolimus structure reveals that it is an immunosuppressive macrolide [1] bearing a stable 2-hydroxyethyl chain substitution at position 40 on the rapamycin structure. Everolimus has the solubility around 192 mg/mL in both dimethyl sulfoxide (DMSO) and ethanol, however it is scarcely soluble in water. And the approximate price of Everolimus is $670 per 100 mg in selleckchem.com and Everolimus price may vary according to the proportion purity of the preparation and/or from one Everolimus supplier to different ones. [Read the Full Post]

DRUG DISCOVERY AND COMPOUND LIBRARIES

3407 views | Sep 29 2012

INTRODUCTION: A large number of compounds stored for the purpose of discovering something beneficial and more efficient we are looking for is known as compound library screening. A compound library is constructed for the purpose of drug discovery and is screened for the best drug by high through put screening techniques of recent era. Compounds included in the library are fully organized by a specific database system containing information about the compounds and their related properties like purity, chemical structure, physical, chemical and pharmacological properties, and the preparation of that compound . Lots of libraries of different compounds are available commercially that contain different common or unique type of biochemical compounds. Description of these compounds and complete information is available in a file named research chemical library which can be bought from the suppliers of relevant compound libraries. [Read the Full Post]

Everolimus, as a mTOR inhibitor

6338 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

3658 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

3120 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

2973 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

2539 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

3259 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

2692 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

2537 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

2980 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

7230 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

4254 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

3201 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

4162 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]