Blog of Signaling Pathways

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

IMPLICATION OF DEREGULATION OF PARP CASCADE: PARP or Poly ADP-ribose polymerase enzymatic proteins are encoded by PARP genes in human, and are responsible of regulating the critical cellular processes for example, programmed cell death and DNA repair channel. They play their role in DNA repair pathway by repairing the single-stranded DNA breaks (ssDNA). The interaction of BRCA1 and BRCA2 with them is very well documented that describes a link between PARP deregulation and ovarian and breast cancer, as many among these cancers are associated with the mutations inside these two genes. This is why the PARP inhibition process has proved to be an attractive therapeutic tool [1] and PARP specific inhibitor molecule may prove highly effective against tumors with BRCAness. Generally PARP selective inhibitor exhibits good results due to the tumor cells beings highly sensitive for PARP inhibitor drug leaving the remaining healthy cells. Hence PARP inhibitor mechanism has made them a better choice as compare to the conventional therapies that must affect all the cells irrespective of their status. > Read the Full Post

SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) OR VORINOSTAT: Functions of HDACi (HDAC inhibitors) is to regulate the gene expression, induction of cell cycle arrest, stimulate apoptosis in cancer cells and modulation of various pathways in tumor cells for example cell proliferation, by hyperacetylating the histone proteins. Due to possessing these abilities, HDAC inhibitors are being used as a very valuable chemotherapeutic anti-cancer agents and SAHA or Vorinostat SAHA is important among them [1]. Vorinostat has found to be possessing strong anti-cancer properties [2] and Vorinostat structure reveals that this molecule is a derivative of hydroxamic acid. For HDAC inhibitors class I and HDACi class II Vorinostat IC50 is found to be near 50 nM. Vorinostat is soluble is ethanol up to 2 mg/ml and in DMSO 65 mg/ml but Vorinostat solubility is found to be very poor in water.> Read the Full Post

PAZOPANIB: INTRODUCTION Pazopanib VEGFR inhibitor is compound manufactured by a famous pharmacuetical company GlaxoSmithKline under the trading name of Votrient, is a potential source of anti-angiogenic activity which inhibits R1, VEGF, VEGF R3 and VEGF R2 along with β subtypes and PDGFR-a and c-kit RTKs. Pazopanib is a small molecule which got famous in recent years when it showed potential activity in various types of tumors. PazopanibVEGFR-PDGFR inhibitor is actually one of those few inhibitor molecules that are approved for their use at clinical levels. Its structure revealed the presence of sulfonamide group in it. One can purchase Pazopanib to supplier Pazopanib under the trading name Votrient or GW786034 by paying the price around $100 for a 25 mg vial. Pazopanib price may vary from supplier to supplier. Pazopanib solubility is very good in DMSO but not in water and ethanol. Its stability is for almost 2 years when stored at -20oC. Pazopanib IC50 for efficient VEGF R1, VEGF -2, VEGF -3 inhibitions is actually 10 nM, 30nM and 47 nM respectively. For closely related kinase enzymes for example PDGFR-FGF R1, c-Kit and c-fms, Pazopanib IC50 was recorded as 85 nM, 140 nM, 74 nM and 146 nM, respectively. > Read the Full Post

TEMSIROLIMUS AND mTOR INHIBITORS:  mTOR protein kinases belonging to phosphatidylinositol 3-kinase (PI3-K) which is related to the family of kinase proteins are responsible to regulate cell growth, survival, proliferation, protein synthesis, cell’s transcriptional activities and cell migration. Because of their influence on all of the above mentioned processes, targeting many of these enzymes for the treatment of various diseases is now a very valuable approach. Previously Rapamycin was found to be the most famous inhibitor belonging to category mTOR but these days another member of same family named as Temsirolimus mTOR inhibitor is also getting popularity. > Read the Full Post

INTRODUCTION: In pharmaceutical industries a famous technique for discovering novel therapeutics is called as High throughput screening. This is also known as High throughput screening assay, various drugs or chemical compounds are analyzed for their potency with respect to their biological, biochemical or pharmaceutical actions by the help of unique and advanced techniques based on automatic machines. This assay has been proven as one of the most effective way of discovering new drugs against specific diseases; examples are enzyme proteins, ligands for various receptors as well as ion channels and a huge number of other pharmaceutical targets. In addition to this application High throughput screening is also being applied for the verification or detection of different biochemical or cellular mechanisms which are under investigations for therapeutic purposes such as inhibitors for different cellular pathways.> Read the Full Post

INTRODUCTION: SRC inhibitors are the molecules specific for targeting the non rector tyrosine kinase enzymes of SRC family and have the potential of inhibiting the 2 or more members of two SRC subfamilies, Fyn, Src. Fgr, Yes, Lck, Blk, Frk and Hck SRC kinases. These kinase enzymes take part in various pathways, so targeting them has became an attractive and valuable approach in the field of chemotherapy. Imatinib is commonly known as STI-571. Imatinib SRC inhibitor is a molecule originally named as STI571 and marketed by the company Novartis in the form of its mesylate salt hence known as STI-571 Imatinib Mesylate. This salt form is especially developed for targeting the cancer cells sparing the normal cells from them hence developed as personalized drug. > Read the Full Post

EPIGENETIC MODULATION BY HDAC INHIBITIORS: Acetylation process of histone proteins performs a major role in various cellular processes for example cellular growth and apoptosis by preventing the transcription of various proteins by the removal of acetyl groups from the histones hence increasing their DNA binding capacity which leads to the formation of a condensed DNA. This strategy goes wrong in case of neurodegenerative diseases and many types of cancers in which any abnormality in this process causes the removal of this block leading to the cells to proliferate in an uncontrolled manner. Then an HDAC inhibitor pathway comes into light and smoothes the progress of HDAC inhibition. The successful revelation of mechanism of HDAC inhibition has led to their extensive use in different clinical and preclinical studies. > Read the Full Post

EVEROLIMUS: Mammalian target of Rapamycin abbreviated as mTOR is a serine/threonine protein kinase enzyme encoded by the FRAP1 gene involving in different transcriptional events, regulation of aging, and in cell invasion, survival and proliferation pathways. In cancers, the Dysregulation of mTOR cascade is a very common event that makes it a promising and attractive target for the anti-tumor therapies [1]. Among those many inhibiting drugs tried for the sake of treating cancers, Everolimus mTOR inhibitor is one of the best [2]. The trade name of this inhibiting drug is Afinitor Everolimus and is marketed by the company Novartis. It is an orally administered medicine and is a derivative of 40-O-(2-hydroxyethyl). Everolimus IC50 is found to be around 1 nM. In Everolimus structure a 2-hydroxyethyl chain at 40th Oxygen molecule improves its pharmacokinetic properties. Everolimus sulobility is best in DMSO (100 mg/ml) and ethanol as it is an oral drug but is also achievable in water. Everolimus price is about $60 for 5 mg vial and the Everolimus suppliers distribute it in the dry ice.> Read the Full Post

GEFITINIB: PROPERTIES AND MECHANISM OF ACTION There are two companies that are marketing Gefitinib named AstraZeneca and Teva. Gefitinib drug is actually Gefitinib EGFR inhibitor molecule that is an efficient and strong compound and has undergone clinical trials. Gefitinib structure reveals that a ring of anilinoquinazoline is present in it. Gefitinib price for a 1 gram vial is around $80 and due to its reasonable price one can purchase Gefitinib EGFR inhibitor very easily for laboratory or research purposes from any supplier Gefitinib. Gefitinib stability is for almost 2 years if stored at -20 degrees. To inhibit Tyr 1173 and Tyr 992 properly, the Gefitinib IC50 is found to be 57 nM and 37 nM respectively for inhibition of EGFR. Various Gefitinib assays were carried out to check the sensitivity and pharmacokinetic properties of this drug and those clinical assays were found to base upon some certain predictive markers like EGFR mutated genes, mutations in K-Ras and copy number. > Read the Full Post