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GEFITINIB; AN EGFR INHIBITOR

4061 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

2168 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

2382 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

3498 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

3292 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

3116 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

2863 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

3967 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

3607 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

5256 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

4587 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

4372 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

5048 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

2332 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]

OBATOCLAX AGAINST BCL-2 PATHWAYS IN CANCER

3111 views | Mar 13 2012

Importance of Bcl-2 Pathway in Cancer: The pro-survival protein Bcl-2 and its related family members activate pro-survival pathways in cancer that are often associated with uncontrolled proliferation of cancer cells. Apart from this direct effect, stress pathways are also reported to be converging with Bcl-2 signaling pathways which makes the development of various Bcl-2 inhibitors an attractive approach to target cancer by inducing mitochondrial apoptotic pathways. [Read the Full Post]

OLAPARIB FOR PARP-1 INHIBITION

3845 views | Mar 13 2012

PARP-1 Inhibition and its Implications in Cancer: The Poly [ADP-ribose] polymerase 1 or PARP-1 proteins have been well documented to be linked with cancers affecting their differentiation, proliferation and transformation. On the other hand, BRCA1 and BRCA2 genes are also well linked with the highly proliferating ovarian and breast cancer and hence the development of PARP-1 inhibitors that can target the aforementioned genes effectively in breast and ovarian cancer cells has been considered as a very attractive and feasible approach. The increasing popularity of PARP-1 inhibitors can be attributed to their specific action against cancer cells while sparing normal cells. [Read the Full Post]

AZD1152 – AN AURORA KINASE INHIBITOR

5112 views | Mar 13 2012

Inhibition of AURORA KINASES in relation to cancer: Mitosis is a key process in the regeneration of cellular material and two key regulators of this function are serine and threonine kinases which are more commonly known as Aurora Kinases. Three isoforms of the aurora kinase have been isolated in human tissue (A,B and C) which function on different aspects of the mitosis cycle. Aurora kinases are significant as targets for chemotherapeutic action since they are elevated in many different cancer types. Small molecule inhibitors of aurora kinases, such as VX-680 (Tozasertib), ZM447439 and Hesperadin, have been developed and successfully trialed on several cancer groups including breast, colon, prostate and in acute myeloid leukemia (AML). [Read the Full Post]

ABT-263: THE BH-3 MIMETIC

4353 views | Mar 13 2012

ABT-263 – Introduction: ABT-263 is a small molecule Bcl-2/Bcl-XL inhibitor marketed by Abbott laboratories under the generic name of Navitoclax. Similar in nature to ABT-737, also marketed by Abbott laboratories, ABT-263 inhibits the anti – intrinsic apoptotic pathway via the BH3 domain. Bcl-2/Bcl-XL bind with pro-apoptotic proteins (BID) with the single BH3 domain and thereby regulate the apoptotic process. However, it has been observed in numerous cancer types that Bcl-2 is over expressed which leads to the survival of cells that would normally be removed via apoptosis. ABT-263 Bcl-2 inhibitor have been demonstrated to be effective against small cell lung cancer xenographs, acute lymphoblastic leukemia and hematologic tumors. [Read the Full Post]

ABT-869 – THE MULTI KINASE INHIBITOR

2703 views | Mar 13 2012

ABT-869 – Tyrosine Kinase Inhibition: Tyrosine kinase is a family of enzymes that utilize phosphorylation of proteins to determine activity of many cellular functions. Tyrosine kinases are a sub family of the protein kinases which phosphorylate serine and threonine for cellular control. Mutation at the genetic level has been observed in this family of enzymes, which leads to the enzyme becoming unregulated. This over expression is observed in many cancer cell lines and represents a target for chemotherapy treatment. Tyrosine kinase inhibitors are novel small molecules which have come to the forefront of cancer research in recent times. Based on the designed molecule Imatinib, TKI’s have been developed to inhibit a wide range of tyrosine kinase receptor either as a single targeted or as a multiple targeted drug. ABT-869 PDGFR inhibitor, marketed under the trade name Linifanib, is a multi-targeted inhibitor against PDGFR-β, KDR, CSF-1R, FLT1, FLT4, KIT, FLT3 and Tie2. [Read the Full Post]