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Blog of Signaling Pathways

Oligomycin A CGMP or cAMP in the lysates were by radioimmunoassay

3649 views | Oct 23 2012

CGMP or cAMP in the lysates were by radioimmunoassay of cGMP from Amersham or with protein kinase type I muscle beef, each determined. Activity t and PIP3 [Read the Full Post]

PI-103, as a potent class I PI3K inhibitor

3352 views | Oct 21 2012

CHARACTERIZATION of PI-103 So far, there are a lot of PI3K isozyme-selective allosteric inhibitors that have been reported. For example, PIK-75 is a p110alpha-specific inhibitor, TGX-221 is a p110beta-specific inhibitor and IC87114 is a p110delta-specific inhibitor. These PI3K inhibitors are promising agents in the treatment of cancer and other diseases, and PI-103 is one of them. PI-103 is a potent, cell-permeable, ATP-competitive class I PI3K inhibitor. The structure analysis indicates that PI-103 is a pyridinylfuranopyrimidine molecule and ATP-competitive PI3K inhibitor. PI-103 has the solubility around 24 mg/mL in both dimethyl sulfoxide (DMSO), however it is scarcely soluble in ethanol and water with solubility of less than 1 mg/mL. And the approximate price of PI-103 is $151 per 10 mg and $466 per 50 mg in selleckchem.com, and PI-103 price may vary according to the proportion purity of the preparation and/or from one PI-103 supplier to different ones. [Read the Full Post]

GDC-0941 as a potent PI3K inhibitor

3204 views | Oct 19 2012

CHARACTERIZATION OF GDC-0941 PI3 kinases are identified as the lipid kinases, which involve in the regulation of breast tumor cell growth, migration, and survival. So far, there are a lot of PI3K isozyme-selective inhibitors that have been reported as the potential therapy drugs against tumors or other diseases, and GDC-0941 is one member of them. GDC-0941 is an orally bioavailable class I selective PI3K inhibitor, and produces the antitumor activity in human cancer cell lines in vitro and in vivo cancer models. GDC-0941 is a thieno[3,2-d]pyrimidine derivatives, and interacts with residues outside the active site of p110. [1] GDC-0941 has the solubility around 103 mg/mL in dimethyl sulfoxide (DMSO) , however it is scarcely soluble in both water and ethanol with solubility of less than 1 mg/mL. And the approximate price of GDC-0941 is $214 per 10 mg and $466 per 50 mg in selleckchem.com, and GDC-0941 price may vary according to the proportion purity of the preparation and/or from one GDC-0941 supplier to different ones. [Read the Full Post]

PI-103, a multi-kinase inhibitor

6296 views | Oct 17 2012

PI-103 According to the critical roles of PI3K for cell growth and survival, a series of isoform-selective inhibitors of the PI3 kinase family, such as PI-103, PIK-90, and TGX-468 are synthesized and identified to block phosphorylation of Akt, the downstream effector of PI3 kinase in cancer cell lines. PI103 is a promising tricyclic pyridofuropyrimidine lead and chemical tool compound, and a potent inhibitor with low IC50 values against recombinant PI3K isoforms including p110alpha, p110beta, p110delta,, and p110gamma. Besides, PI-103 also produces effective inhibitory activity against mTORC1 and DNA-PK in the low concentration. In preclinical studies, PI-103 potently inhibits proliferation and invasion of human cancer cells, and shows antiangiogenic potential. Moreover, PI-103 also enhances the induction of mitochondrial apoptosis by enhances downstream p53 signaling . [Read the Full Post]

MK-2206, a potent Akt inhibitor

5953 views | Oct 16 2012

Characterization of MK-2206 Akt is identified as a serine-threonine kinase on the basis of its homology to protein kinase A (PKA), protein kinase C (PKC) and the retroviral oncogene, viral Akt. The known three human AKT isozymes (Akt1, Akt2 and Akt3) are highly homologous multi-domain proteins with both overlapping and distinct cellular functions. So far, there are a lot of AKT isozyme-selective allosteric inhibitors that have been reported, and MK-2206 is one member of them. MK-2206 is a potent, oral allosteric inhibitor of all AKT isoforms, which binds to a site outside the PH domain and binds very weakly to the PH domain of Akt. MK-2206 has the solubility around 96 mg/mL in both dimethyl sulfoxide (DMSO) and water, however it is scarcely soluble in ethanol with solubility of 2 mg/mL. And the approximate price of MK-2206 is $214 per 10 mg and $718 per 50 mg in selleckchem.com, and MK-2206 price may vary according to the proportion purity of the preparation and/or from one MK-2206 supplier to different ones. [Read the Full Post]

Perifosine as a potent Akt inhibitor

4294 views | Oct 15 2012

FEATURES OF PERIFOSINE Perifosine, also known as KRX-0401, is a synthetic novel alkylphospholipid (ALP) and a potent antitumor agents which inhibits PH domain mediated AKT membrane recruitment and activation. Perifosine structure has been elucidated through X-ray crystallography and it shows the similar structure with phospholipids that are the main constituents of cellular membranes. Perifosine is soluble in water and ethanol with solubility of 14 mg/mL and 92 mg/mL, respectively. But Perifosine solubility in DMSO is poor. Commercially researchers can obtain Perifosine with the price of about $210/mg from suppliers selleck chemicals. Perifosine stability keeps good for at least 2 years for the dry solid when stored at -20°C and for 6 months at -80°C in DMSO. [Read the Full Post]

HIGH THROUGHPUT SCREENING HELPING THE DRUG DISCOVERY

3468 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

9491 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

3212 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

7011 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

3675 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

3447 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

6464 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

3716 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

3145 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

3018 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

2572 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

3294 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

2719 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]