Blog of Signaling Pathways

DASATINIB- A DRUG OF CHOICE

7022 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

3957 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

6866 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

3109 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

3106 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

4885 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

2593 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

2895 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

4000 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

3748 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

3652 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

3230 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

4576 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

4135 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

5823 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

5135 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]

SORAFENIB: THE MULTIKINASE INHIBITOR

0 views | Mar 20 2012

INTRODUCTION: By using multi-kinase inhibitors, more than one kinase enzyme at a time can be targeted so their use is considered to be very important and practicable approach for the treatment of cancers. Hence the use of a single inhibitor molecule having pan-tyrosine kinase ability is very attractive to target different overexpressed tyrosine kinases simultaneously. A lot of such inhibitor molecules are being used for this purpose which is showing very promising results in clinical trials. The property of Sorafenib VEGFR inhibitor is that it targets many other receptor molecules other than VEGFR. Sorafenib B-RAF inhibitor inhibits different pathways like Raf/MEK/ERK very efficiently which approves it’s as a multi-kinase inhibitor. [Read the Full Post]

OLAPARIB: THE FIRST PARP INHIBITOR

5087 views | Mar 19 2012

Introduction: PARP Inhibition Signaling activities within the cell are conducted along set pathways of protein – protein interactions. Depending on the cell status and the ligands triggering the signaling cascade to what function is carried out in the nucleus. A protein located in the nucleus has been established to be the principle regulator of the apoptosis and repair functions of certain DNA damage. This protein is called “Poly (ADP-ribose) polymerase” or it is abbreviated to “PARP”. The PARP family of proteins is extensive with 17 members currently known and the range of effects of PARP activity is large. The general structure of the PARP series of proteins contains four different types of binding domains which dictate the activity, one of the domains is referred to as the catalytic domain contains an amino acid sequence that is identical between all the members of the protein family. The mechanism of action of PARP proteins is to add a series of ADP ribose molecules to the protein ligands, the number and site of this addition controls the response of the affected protein. [Read the Full Post]

U0126: THE MOST POTENT MEK INHIBITOR

5868 views | Mar 18 2012

The MAPK pathways In ever cells life span there are circumstances when the cell is placed in a stressful situation, such toxic shock, injury to the surrounding tissue or old age. In such circumstances the cells must react either to die or to live and grow. The regulation of this process is the responsibility of the “Mitogen-activated protein kinases (MAPK)”. The MAP kinases are involved in a broad spectrum of processes covering proliferation (mitosis), apoptosis, cell migration/motility and gene expression. The MAP kinases are located in the cell membrane and on receipt of an external extracellular signal any one of three pathways can be stimulated, these are the ERK, JNK or the P38MAPK pathways. [Read the Full Post]

TEMSIROLIMUS

2843 views | Mar 18 2012

Introduction: mTOR inhibitiors The mTOR kinase is part of the same pathway as AKT and PI3K, this signaling pathway is a tyrosine kinase sub family of the super protein kinase family. The PI3K/AKT/mTOR signaling cascade is involved in a variety of cellular functions such as migration, growth, protein synthesis, survival and proliferation. PI3K and AKT inhibitors have all been reported as having significant potential as treatments against disorders involving cell growth, mTOR is part of the same pathway and theoretically would make a potential target for inhibition. It has also been reported that mutations in the mTOr signaling have been implicated in cardiovascular disease, cancer and disorders of the metabolism. Rapamycin was the first mTOR inhibitor to be released but was quickly followed by a 2nd generation analogue Sirolimus. Temsirolimus is a 3rd generation molecule designed to be an improvement over rapamycin and Sirolimus. Temsirolimus has demonstrated potential in the treatment of renal carcinomas, NSCLC and malignant glioma. [Read the Full Post]