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Blog of Signaling Pathways

SORAFENIB-AS A MULTIKINASE INHIBITOR

3162 views | Jun 08 2012

SORAFENIB For receiving extracellular or intracellular stimulus numerous types of non-receptor and receptor tyrosine kinases are present in cells which are capable of conducting inhibitory and initiatory action on different signalling pathways. Defect of any type in these processes can cause cancer. The kinases which are involved in the over-expression or under expression of gene that are cause of cancer can be used as target for cancer therapy. Different types of kinases are being inhibited by employing only one inhibitor. Due to the involvement of abnormal tyrosine kinase in the development of cancer inhibitors of tyrosine kinases are being developed and studied to use it as for the treatment of cancer. Clinical trials of different inhibitors have shown outstanding results. Among these inhibitors one important inhibitor is Sorafenib inhibitor which has shown to inhibit kinases excluding respective VEGFR. Similarly Raf pathway/ERK/MEK pathway have been found inhibited by the administration of Sorafenib Raf inhibitor. [Read the Full Post]

ROLE OF HIGH THROUGHPUT SCREENING IN DRUG DISCOVERIES

3127 views | Jun 07 2012

INTRODUCTION: High throughput screening is one of the novel and leading technique for the discoveries of new pharmaceutical agents for the treatment of various lethal diseases. This famous technique is also called as the High throughput screening assay, this technique has been so impressive and fast due to the advancements in automatic machines. This technique is based on the properties of different chemical agents for their ability under pharmaceuticals, biochemical and biological actions against any disorder. In the era of drug discovery this technique has been proved as the most effective for the treatment of specific diseases and these treatments are based on the drugs discovered as ligands for receptors, enzymes, proteins and ion channels. High throughput screening is also used for the detection and study of cellular or biochemical pathways for the assessment of the certain therapeutics for respective cellular mechanisms. The major example includes screening library of kinases and this is leading applied example in this regard in comparison to old methods. The importance of High throughput screening can be analyzed by studying reviews of this novel method for discovering new drugs. Business of pharmaceuticals and science and research has been greatly benefited by this method. [Read the Full Post]

PAZOPANIB: LATEST VEGFR INHIBITOR

3372 views | Jun 06 2012

PAZOPANIB: INTRODUCTION One of the very important anti-tumor drugs Pazopanib VEGFR inhibitor also known as Pazopanib Votrient is being produced by the very popular pharmaceutical company which is GlaxoSmithKline. It is selling this drug with commercial name of Votrient. Pazopanib inhibits the angiogenesis by blocking VEGF R1, R2 and R3 with their β subtypes and also inhibits c-kit RTKs as well as PDGFR-a. Though Pazopanib is tiny molecule yet it gains popularity due to its extensive potential on various kinds of malignancies. PazopanibVEGFR-PDGFR inhibitor has now been approved to enter the clinical trials. It was revealed by the Pazopanib structure that it contained a sulfonamide group. It is marketed in 25mg of packaging with Pazopanib price of approximately $100 as Votrient or GW786034 and anyone can buy Pazopanib for research or experimental purposes from supplier Pazopanib. Prices are being varied from supplier to supplier. Pazopanib solubility revealed it is best soluble in DMSO while it is absolutely insoluble in water and ethanol. [Read the Full Post]

EVEROLIMUS-AN mTOR INHIBITOR

2668 views | Jun 05 2012

mTOR PATHWAY AND EVEROLIMUS Regulatory activities of the cell that are related to its multiplication, movement, transcription and as well as translation of the genes is controlled by mTOR pathway which is one of the important various cell cycle regulators. FRAP1 gene is translated to produce mTOR which phosphorylates serine/threonine residue of proteins. Cancer usually arises from the down-regulation of this mTOR cascade. So for targeted cancer therapy proteins like it are also taken under consideration [1].Different types of inhibitors are being searched and Everolimus mTOR inhibitoris one of the very promising inhibitors [2]. Novartis which is pharmaceutical company produced it and sell it with as Afinitor Everolimus which is its trade name. Since structural studies revealed that Everolimus is a derivative of 40-O-(2-hydroxyethyl), the pharmacokinetic properties are seemed to be improved due to the availability of oxygen atom the 40 position. Against mTOR Everolimus IC50 is approximately 1nM.Around 100mg/ml of DMSO is suitable for Everolimus solubility. It is water and ethanol soluble. The mode of administration of Everolimus is through 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]

DASATINIB- A DRUG OF CHOICE

5828 views | Jun 04 2012

INTRODUCTION Diverse types of cellular systems are there in human bodies that differ structurally and functionally from one another. Each cellular system is controlled by a variety of controllers called cell cycle regulatory proteins. Defective controllers may lead to abnormal cellular systems and the condition known as cancer may develop. Cancer may be of different types depending upon the defect in the cell cycle regulatory proteins. Cancer may also vary on the basis of stage of the defective condition. Many therapies have been devised in order to treat cancerous cells. Further research is also being done for developing better, more specific and less toxic therapies and to cope with the development of resistance in the defective cells against existing therapies. Besides resistance, metastasis is also another issue to be resolved in case of cancerous cells. Imatinib has been used against leukemia for several years but due to high levels of toxicity scientists discovered a new drug, called Dasatinib, for the same therapy. Dasatinib BMS-354825 is more efficient and less toxic as compared to Imatinib. The drug is being marketed by the name of Sprycel. As Dasatinib was discovered by Jagabandhu Das, it was named Dasatinib. Development of the drug was done by Squibb Company. [Read the Full Post]

RALTEGRAVIR- FAMOUS INTEGRASE INHIBITOR

3428 views | Jun 03 2012

INTEGRASE IN CASE OF HIV-1 The most deathly disease on earth, HIV-I, is being researched and studied a lot to find out an effective therapy against it. This virus contains some genes for enzymes/proteins and utilizes some others from the host cells. The enzyme in HIV that helps the virus to integrate its genome into host cell/genome is named as Integrase and gets replicated there. To search for the [roper treatment the first thing that must be keep in mind is resistance development by the mutation of their genes during replication, so it is the need of hour that the research about treatment of cancer must go on further and should be regularly updated. To inhibit their enzymatic activity is an attractive approach. The inhibitors for integrase enzyme have been developed and they inhibit the process of integration of viral genome into the host genome hence prevent its proliferation in the hosting cell. A huge wave of research is going on HIV-I regarding integrase inhibitors that offer promising results against HIV-I virus. Raltegravir integrase inhibitor is such an inhibitor that inhibits the integrase enzyme and it is the first inhibitor to get approved from FDA and its discovery is no doubt considered to be a great blessing. [Read the Full Post]

NILOTINIB

5753 views | May 30 2012

ROLE OF BCR-ABL TYROSINE KINASES IN CML: A chimeric BCR-ABL oncogene is obtained by the fusion of Abelson (ABL) tyrosine kinase (TK) gene and break-point cluster (BCR) gene, and here TK has been related to pathogenesis of CML (Chronic Myelogenous Leukemia), 90% of this debilitating disease involves chromosomal abnormalities leading to formation of so-called Philadelphia chromosome. As there is a confirmed participation of BCR-ABL TK in PH+ CML, different inhibitors that target this TK have registered remarkable success in treatment of CML and among them Nilotinib bcr-abl inhibitor is the most valuable one. It is a form of tyrosine kinase inhibitor and is a hydrochloride monohydrate salt. [Read the Full Post]

SUNITINIB: THE MULTI-TARGETED APPROACH

2824 views | May 31 2012

MUTIKINASE INHIBITORS IN CHEMOTHERAPEUTICS:  Different types of metabolic systems that occur between varieties of cells are mediated through a class of enzymes called tyrosine kinases. Since these tyrosine kinases play important role in processes e.g. division, survival, multiplication, differentiation, growth and death of cell, their inhibition have been found very promising target. By doing any change in them the processes which they regulate can also be down regulated. This behaviour is being exploited as inhibitors of tyrosine kinases for chemotherapy. The inhibitors of tyrosine kinases block multiple kinases at the same time. The involvement of tyrosine kinases in the pathways which cause different cancers like it is involved in vascular endothelial growth factor pathway in case of breast cancer and many other types of cancer makes them interesting. [Read the Full Post]

RAD001 – THE mTOR INHIBITOR

2775 views | May 29 2012

RAD001: The mTOR protein which is also known as Rapamycin’s mammalian target protein is famous threonine or serine protein kinase enzyme. This kinase plays several significant roles including cellular survival, cell division, migration of cells and also in regulating a good numbers of transcriptional events linked to a huge number of signaling cascades such as aging. There are several research reports mentioning the involvement of abrupt mTOR pathway in cancer and tumorigenesis, due to this fact this pathway has become a target for the cure of large number of cancers [1]. Different mTOR inhibitors has been generated and tested, amongst these inhibitors RAD001 mTOR inhibitor is orally bio-available chemical [2]. This is developed by Novartis and is recognized under the name, Everolimus. RAD001 can be purchased easily from RAD001 supplier. According to the RAD001 structure it contains 40-O-(2-hydroxyethyl) but it is a derivative of this compound in order to enhance its pharmacokinetics. For appropriate inhibition of mTOR pathway RAD IC50 is about 1nM. The RAD001 solubility can be gained in ethnol and water as well where as a 100mg/ml solution can be gained in DMSO. If someone wants to purchase RAD001 on can pay RAD001 price of 50$ and get a vial of 5mg. One main property of this compound is its action on mTOR1 pathway rather than mTOR2 pathway as it does not affect. [Read the Full Post]

GEFITINIB; AN EGFR INHIBITOR

3982 views | May 28 2012

PROPERTIES AND MODE OF ACTION Gefitinib is one of several tyrosine kinase inhibitors that are quite efficient in their activity. Gefitinib is actually an EGFR inhibitor. It is marketed by the two companies i.e., Teva and AstraZeneca. Gefitinib EGFR inhibitor is a strong inhibitory compound and Gefitinib structure shows the presence of a ring in it i.e., anilinoquinazoline. One can buy Gefitinib in the form of a 1 gm vial in approximately $80. Scientists can purchase Gefitinib for research or treatment purposes. Gefitinib solubility can be achieved in organic solvents like ethanol, DMSO and DMF and Gefitinib stability for approximately 2 years can be achieved if it is stored at -20 oC. Gefitinib IC50 for EGFR inhibition against Tyr 992 and Tyr 1173 is 37 nM and 57 nM respectively. Different types of assays have been designed to clinically analyze the pharmacokinetics and sensitivity of the drug. These assays are based upon some predicting markers e.g., EGFR mutated genes, copy number or K-Ras mutations. [Read the Full Post]

TEMSIROLIMUS

2156 views | May 27 2012

TEMSIROLIMUS: mTOR INHIBITOR mTOR protein kinase enzymes are the proteins that belongs to PI3-K (phosphatidylinositol 3-kinase) which is associated with the family of kinase proteins and are responsible for regulation of cell survival, growth, proliferation, transcriptional activities, cell migration and protein synthesis. Just because of the effect of these inhibitors on the above mentioned phenomenon, the targeting of these enzymes to treat various types of cancers is now an attractive approach. In past Rapamycin was known to be the most valuable inhibiting drug that belongs to the class of mTOR inhibitors but now days another member of this family named Temsirolimus mTOR inhibitor is more famous than that one. [Read the Full Post]

EVEROLIMUS-AN mTOR INHIBITOR

2361 views | May 25 2012

mTOR PATHWAY AND EVEROLIMUS Among different cell cycle regulatory pathways, mTOR pathway is an important one as it is involved in a lot of regulatory activities related to cell proliferation, growth, migration and activities related to transcription and translation. mTOR is actually serine/threonine protein kinase that is a product of FRAP1 gene. Defected or dysregulated mTOR pathway is a common reason of developing cancerous cells. Therefore, these proteins are also targeted while looking for an effective anti-cancer therapy [1]. For this purpose many inhibitors against these proteins are being researched. One of these efficiently acting inhibitors is the Everolimus mTOR inhibitor [2]. It is marketed by pharmaceutical company Novartis and is available under the trade name of Afinitor Everolimus. Everolimus structure is a 40-O-(2-hydroxyethyl) derivative where oxygen at position 40 is known to improve its pharmacokinetic properties. Everolimus IC50 against mTOR is around 1 nM. Everolimus solubility can be achieved upto 100 mg/ml in DMSO. It is also soluble in ethanol and water. Everolimus is an orally administered drug and is available in the form of a vial of 5 mg with an Everolimus price of around $60. It is distributed in dry ice. [Read the Full Post]

SUNITINIB: A MULTI-KINASE ENZYME INHIBITOR

3451 views | May 24 2012

TYROSINE KINASE INHIBITORS Tyrosine kinase enzymes are very important amongst the diversified world of proteins involving the signal transduction process for their role in various processes like inhibition or activation of genes expression responsible for cell growth, cell division, cell differentiation and cell death. Abnormalities in these tyrosine kinases are leading cause of in the disruption in above mentioned functions stimulating the tumor development. The inhibition of tyrosine kinase enzyme is an attractive target when there is the disruption in any cell cycle regulatory enzyme affected by the tyrosine kinase in case of any kind of cancer. So these enzymes are the attractive target for anti-tumor drugs as they are those that start the function. Tyrosine kinase inhibitors are having the ability of affecting different kinds of tyrosine kinase enzymes hence called as multikinase inhibitors and they may be non-receptor or receptor kinases. If the type of kinase involving in the cancer condition is known, like for VEGF involved in the breast cancer, the medicine for choice must be a TKI. [Read the Full Post]

SUNITINIB: THE MULTI-TARGETED APPROACH

3243 views | May 23 2012

MUTIKINASE INHIBITORS IN CHEMOTHERAPEUTICS: Tyrosine kinases are the enzymes which act as mediators between different cells to facilitate variety of metabolic processes in the cells. The inhibition of these enzymes is found to be a very attractive target due to their prime role in various important processes in the cells for instance cellular growth, survival, proliferation, apoptosis and differentiation. Any type of modulation of these enzymes can cause the downstream regulation of the pathways controlled by them. This is why inhibitors to tyrosine kinases are getting very famous as chemotherapeutic agents. Many tyrosine kinase inhibitors are multikinase inhibitors as they can inhibit more than one type of tyrosine kinase enzymes. VEGF pathway involvement in breast carcinoma and some other tyrosine kinases in other cancers made these enzymes a popular interest. Tyrosine kinase inhibitors are used successfully against solid form tumors and various multi tyrosine kinase inhibitors are used for treating gastrointestinal stromal tumors. Tyrosine kinase inhibitors are also employed for the treatment against acute form of lymphoblastic leukemia. [Read the Full Post]

PAZOPANIB: LATEST VEGFR INHIBITOR

3061 views | May 22 2012

PAZOPANIB: INTRODUCTION A very famous pharmaceutical company named GlaxoSmithKline is the manufacturer of an important anticancer drug Pazopanib Votrient known as Pazopanib VEGFR inhibitor and is selling it under the trade name Votrient. Pazopanib is a good source of anti-angiogenic activity that inhibits VEGF, R1, VEGFR2 and VEGFR3 along with the β subtypes and c-kit RTKs and PDGFR-a. Pazopanib is a very small molecule that got fame in just in recent years by exhibiting its potential activity in case of different types of cancers. PazopanibVEGFR-PDGFR inhibitor is indeed one of those important inhibitors which are now approved for the use at clinical level [1]. Pazopanib structure reveals the presence of a sulfonamide group. One can buy Pazopanib from supplier Pazopanib by paying Pazopanib price that is around $100 per a 25 mg packing under the trade name Votrient or GW786034. Its price may vary among the suppliers. Pazopanib solubility is best observed in DMSO but it is completely insoluble in ethanol and water. It is stable for almost two years if stored at -20oC. [Read the Full Post]

SORAFENIB-AS A MULTIKINASE INHIBITOR

2843 views | May 21 2012

SORAFENIB Various kinds of receptor and non-receptor kinase enzymes are there in the cells that are responsible of carrying out the signaling pathways of initiation or inhibition of cascades after getting intra or extracellular stimulus. Any sort of defect in this process may cause cancer. Inhibition of kinase enzymes to prevent some mal-expressed or over-expressed gene causing tumor is found to be an effective approach. Many multiple kinases can be inhibited by using a single inhibitor. Various types of inhibitors against these kinase proteins are being discovered and studied in order to develop some effective anti-cancer therapy, as many of the tyrosine kinase abnormalities used to become the cause of development of cancer. Many of them are giving promising results in their clinical trials. An important example of these inhibiting drugs is Sorafenib VEGFR inhibitor that has been found to inhibit the protein kinases except respective VEGFR. In the same way Sorafenib Raf inhibitor also an important drug used for the inhibition of MEK/ERK/Raf pathway. [Read the Full Post]

DASATINIB; AN ANTI-RTK DRUG

3940 views | May 16 2012

DASATINIB AND ITS PROPERTIES The high rate of deaths due to cancer and the development of resistance in the cancerous cells for existing drugs are encouraging the scientists and researchers to look for more efficient drugs. Occurrence of different types of mutations makes the cancerous cells to evade the drugs’ action against them. Metastasis is another problem in cancer that complicates the issue. Toxicity is another that is raised in cancer chemotherapy, therefore considering all of the developing complexities, new drugs are quite necessary to be discovered and developed. In case of leukemia, Imatinib had been used since long but due to the complexities associated with this drug, as mentioned above, led the scientists to look for another less toxic and more efficient drug. Jagabandhu Das was the discoverer of a drug in this regards i.e., Dasatinib named so after its discoverer. Dasatinib BMS 354825 got very popular because of lesser toxicity and more efficacies as compared to that of imatinib. It was developed by the company Squibb and is sold under the name of Sprycel. [Read the Full Post]

BORTEZOMIB; INHIBITING PROTEIN DEGRADATION

3568 views | May 17 2012

BORTEZOMIB Poteasomes are one of the very important small organelles present in the cell. They have an important role in cell cycle regulation by degrading un-necessary proteins present in the cell. Sometimes in cancerous cells, the proteins that play a role in inhibiting un-regulated proliferation of cells are degraded by proteasomes. Inhibition of proteasomes in order to inhibit un-regulated growth is an attractive target in cancer therapy. Different proteasome inhibiting compounds have been used conventionally for the treatment of cancer e.g., green tea having Epigallocatechin-3-gallate (EGCG), Salinosporamide-A and Disulfiram. Bortezomib is the first proteasomal inhibitor that has got approval for clinical studies for the treatment of cancer. [Read the Full Post]

RO4929097 – CHECKS NOTCH SIGNALING IN CANCERS

5211 views | Mar 20 2012

RO4929097: A GAMMA SECRETASE INHIBITOR: Among well known proteases Gamma secretase is one which is made up of various subunits. This is present in the membrane hence is a protein in membrane which is also capable of cleaving certain transmembrane proteins therefore also known as the intramembrane protease. In case of Alzheimer’s disease amyloid plaques are formed in brain, these plaques are resulted due to the amyloid beta peptide and these peptides are produced due to the action of gamma secretase, this is one of the well known examples of this protease. Presently, we are focusing on the important role of gamma secretase in the Notch protein processing. In case of many cancers and tumors this Notch protein signaling is found to be abnormal, therefore the arresting of this pathway can be an authentic way to get rid of abnormal cell growth. In the light of this idea a novel RO4929097 gamma secretase inhibitor is discovered. The inhibitory effect of this inhibitor has been confirmed by various methods like western blotting. [Read the Full Post]

SB-431542 – MEDIATES ALK INHIBITION

4548 views | Mar 20 2012

ALK (ANAPLASTIC LYMPHOMA KINASE) RECEPTOR: Anaplastic lymphoma kinase or ALK is encoded by ALK gene and it is also called as CD246 (Cluster of Differentiation-246). This kinase is famous for the brain development but by the genetic fusion of any other gene it can be an oncogenic gene, another reason for its genetic variability is due to the normally found mutations of DNA. In case of ALCLs or large cell lymphomas, NPM (nucleophosmin) is present in fusion form with ALK and this is responsible for the 60% of this cancer. In some of the other cancers like NSCLC (non-small cell lung cancer) and most of adenocarcinomas, the ALK-EML4 fused genes are found as the main cause of tumor formation. Similarly in a pediatric cancer that is known as neuroblastoma, mutated ALK is reported as the main reason in various studies. All of these important examples enlighten the significance of this pathway in different cancers and tumors therefore the discovery or development of such compounds which inhibit the ALK TKs pathway is important. Certain approved inhibitors like Crizotinib used for lung cancer treatment enhances the uses of different inhibitors found in inhibitor library including SB-431542 ALK inhibitor. [Read the Full Post]