Silmitasertib
Silmitasertib (INN), codenamed CX-4945, is a small-molecule inhibitor of protein kinase CK2 (casein kinase II), a constitutively active serine/threonine-specific protein kinase that is overexpressed in several types of tumors. Silmitasertib is in clinical trials for use as an adjunct to chemotherapy in the treatment of cholangiocarcinoma (bile duct cancer), is in phase I and II clinical trials for the treatment of recurrent Sonic Hedgehog (SHH) medulloblastoma, and in preclinical development for other cancers, including hematological and lymphoid malignancies. In January 2017, it was granted orphan drug status by the U.S. Food and Drug Administration for advanced cholangiocarcinoma. It is being developed by Senhwa Biosciences of Taiwan. Mechanism of action Silmitasertib interacts competitively with the ATP-binding site of CK2 subunit alpha. This leads to inhibition of several downstream signaling pathways, including PI3K/Akt. COVID-19 infections In SARS-CoV-2 (COVID-19) i ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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Casein Kinase 2
Casein kinase 2 ()(CK2/CSNK2) is a serine/threonine-selective protein kinase that has been implicated in cell cycle control, DNA repair, regulation of the circadian rhythm, and other cellular processes. De-regulation of CK2 has been linked to tumorigenesis as a potential protection mechanism for mutated cells. Proper CK2 function is necessary for survival of cells as no knockout models have been successfully generated. Structure CK2 typically appears as a tetramer of two α subunits; α being 42 kDa and α’ being 38 kDa, and two β subunits, each weighing in at 28 kDa. The β regulatory domain only has one isoform and therefore within the tetramer will have two β subunits. The catalytic α domains appear as an α or α’ variant and can either be formed in a homodimer (α & α, or α’ & α’) formation or heterodimer formation (α & α’). It is worth noting that other β isoforms have been found in other organisms but not in humans. The α subunits do not require the β ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Casein Kinase 2, Alpha 1
Casein kinase II subunit alpha is an enzyme that in humans is encoded by the ''CSNK2A1'' gene. Casein kinase II is a serine/threonine protein kinase that phosphorylates acidic proteins such as casein. The kinase exists as a tetramer and is composed of an alpha, an alpha-prime, and two beta subunits. The alpha subunits contain the catalytic activity while the beta subunits undergo autophosphorylation. The protein encoded by this gene represents the alpha subunit. While this gene is found on chromosome 20, a related transcribed pseudogene is found on chromosome 11. Three transcript variants encoding two different proteins have been found for this gene. Interactions Casein kinase 2, alpha 1 has been shown to interact with: * APC, * ATF1, * ATF2, * C-Fos, * C-jun, * CDC25B, * CHEK1, * CREBBP, * CSNK2B, * DDIT3, * FGF1, * FGF2, * HNRPA2B1 * MAPK14, * PIN1, * PLEKHO1, * PTEN, * RELA, * TAF1, and * UBTF Nucleolar transcription factor 1 is a protein that in huma ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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Cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown. In 1963, Estabrook, Cooper, and Rosenthal described the role of CYP as a catalyst in steroid hormone synthesis and drug metabolism. In plants, these proteins are important for the biosynthesis of defensive compounds, fatty acids, and hormones. CYP enzymes have been identified in all kingdoms of life: animals, plants, fungi, protists, bacteria, and archaea, as well as in viruses. However, they are not omnipresent; for example, they have not been found in ''Escherichia coli''. , more than 300,000 distinct CYP proteins are known. CYPs are, in general, the terminal oxidase enzymes in electron transfer chains, broadly categorized as P450-containing systems. The term "P450" is derived fro ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via routes other than intravenous, its bioavailability is generally lower than that of intravenous due to intestinal endothelium absorption and first-pass metabolism. Thereby, mathematically, bioavailability equals the ratio of comparing the area under the plasma drug concentration curve versus time (AUC) for the extravascular formulation to the AUC for the intravascular formulation. AUC is used because AUC is proportional to the dose that has entered the systemic circulation. Bioavailability of a drug is an average value; to take population variability into account, deviation range is shown as ±. To ensure that the drug taker who has poor absorption is dosed appropriately, the bottom value ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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Pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, pesticides, food additives, cosmetics, etc. It attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is completely eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics (PD) is the study of how the drug affects the organism. Both together influence dosing, benefit, and adverse effects, as seen in PK/PD models. Overview Pharmacokinetics describes how the body affects a specific xenobiotic/chemical after administration through the mechanisms of absorption and distribut ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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Naphthyridine
Diazanaphthalenes are a class of aromatic heterocyclic chemical compounds that have the formula C8H6N2. They consist of a naphthalene double ring in which two of the carbon atoms have been replaced with nitrogen atoms. There are ten positional isomers, which differ by the locations of the nitrogen atoms. The group consist of two subgroups: *four ''benzodiazines'' with both N atoms in one ring: cinnoline, quinazoline, quinoxaline, and phthalazine Phthalazine, also called benzo-orthodiazine or benzopyridazine, is a heterocyclic organic compound with the molecular formula C8H6N2. It is isomeric with other naphthyridines including quinoxaline, cinnoline and quinazoline. Synthesis Phthalazin ... *six ''naphthyridines'' with one N atom in each ring Isomers References {{reflist ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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PARP Inhibitor
PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP). They are developed for multiple indications, including the treatment of heritable cancers. Several forms of cancer are more dependent on PARP than regular cells, making PARP (PARP1, PARP2 etc) an attractive target for cancer therapy. PARP inhibitors appear to improve progression-free survival in women with recurrent platinum-sensitive ovarian cancer, as evidenced mainly by olaparib added to conventional treatment. In addition to their use in cancer therapy, PARP inhibitors are considered a potential treatment for acute life-threatening diseases, such as stroke and myocardial infarction, as well as for long-term neurodegenerative diseases. Medical uses Approved for marketing * Olaparib: In December, 2014, the EMA and US FDA approved olaparib as monotherapy (at 400 mg taken twice per day) for patients with germline BRCA mutated (gBRCAm) advanced ovarian canc ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Lead Compound
A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the metallic element lead) in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but may nevertheless have suboptimal structure that requires modification to fit better to the target; lead drugs offer the prospect of being followed by back-up compounds. Its chemical structure serves as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters. Furthermore, newly invented pharmacologically active moieties may have poor druglikeness and may require chemical modification to become drug-like enough to be tested biologically or clinically. Terminology Lead compounds are sometimes called developmental candidates. This is because the discovery and selection of lead compounds occurs prior to preclinical and clinical development of the candidate. Discovering lead compo ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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Molecular Modification
Molecular modification is chemical alteration of a known and previously characterized lead compound for the purpose of enhancing its usefulness as a drug. This could mean enhancing its specificity for a particular body target site, increasing its potency, improving its rate and extent of absorption, modifying to advantage its time course in the body, reducing its toxicity, changing its physical or chemical properties (like solubility) to provide desired features. Modification for water solubility Molecular modification is used to enhance drug's water solubility by incorporating water solubilizing groups in its structure. The discussion of the introduction of water solubilizing groups into the structure of a lead compound can be conveniently broken down into four general areas: * The type of group introduced; * Whether the introduction is reversible or irreversible; * The position of incorporation; and * The chemical route of introduction. The type of group The incorporation of ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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Drug Design
Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques. This type of modeling is sometimes referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design. In addition to small molecules, biopharmaceuticals including peptides and especially therapeutic antibodi ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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National Institutes Of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government The federal government of the United States (U.S. federal government or U.S. government) is the national government of the United States, a federal republic located primarily in North America, composed of 50 states, a city within a fede ... responsible for biomedical and public health research. It was founded in the late 1880s and is now part of the United States Department of Health and Human Services. The majority of NIH facilities are located in Bethesda, Maryland, and other nearby suburbs of the Washington metropolitan area, with other primary facilities in the Research Triangle Park in North Carolina and smaller satellite facilities located around the United States. The NIH conducts its own scientific research through the NIH Intramural Research Program (IRP) and provides major biomedical research fundin ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |