Med-Chemist : "Quintessential Medicinal Chemistry"
Monday, January 21, 2013
Sunday, January 20, 2013
Tamoxifen can counteract some pathologic features in mouse model of DMD
In continuation of my update on Tamoxifen
Using the mdx5Cv mouse model of DMD, investigators found that tamoxifen, given orally for more than a year, "caused remarkable improvements of muscle force and of diaphragm and cardiac structure," according to lead author Olivier M. Dorchies, PhD, of the Department of Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences of the University of Geneva and University of Lausanne. For instance, in the heart, fibrosis was diminished by approximately 50%. In the diaphragm, the muscle of the dystrophic mouse thought to be most like that of human DMD, tamoxifen reduced fibrosis while increasing thickness as well as the number and average diameter of muscle fibers. The net effect was that tamoxifen raised the amount of contractile tissue available for respiration by 72%.
Patients with DMD show muscle degeneration, and their muscle fibers become abnormally susceptible to stress. In this animal study, tamoxifen improved the structure of leg muscles, slowed muscle contraction, increased overall muscle function, and made leg muscles more resistant to repetitive stimulation and fatigue. In fact, tamoxifen rendered dystrophic muscles even stronger than those of non-dystrophic control mice. "Our findings of a slower rate of contraction and an enhanced resistance to fatigue in muscles from tamoxifen-treated dystrophic mice are of significance for the pathophysiology of muscular dystrophy," say the authors.
More : http://www.journals.elsevierhealth.com/periodicals/ajpa/article/S0002-9440%2811%2901061-3/abstract
p53 activation suppresses malic enzyme expression and leads to senescence in pre-cancerous cells
A team of researchers from the Perelman School of Medicine, University of Pennsylvania, has identified a class of p53 target genes and regulatory molecules that represent more promising therapeutic candidates. Researchers describes that, p53 participates in a molecular feedback circuit with malic enzymes, thereby showing that p53 activity is also involved in regulating metabolism.(The Yang lab identified p53's role in glucose metabolism in the past.)
The new findings, Yang (lead researcher) says, suggest that p53 acts as a molecular sensor of metabolic stress and explains how metabolic stress can lead to senescence in cells.
"We uncovered an important regulatory mechanism for p53 as well as an effector mechanism for p53," Yang says.
Significantly, the findings also identify malic enzymes as novel and potentially useful pharmaceutical targets for anticancer therapy, as well as possible mediators of the normal aging process though neither possibility was actually addressed in the current study.
As cells become damaged and precancerous, the p53 protein prevents those cells from continuing towards becoming tumors by causing the cells to senesce. Metabolic cues also regulate senescence, but the molecular relays coupling those two processes, senescence and metabolism remained unknown................
Saturday, January 19, 2013
Diospyrin inactivates a drug target for tuberculosis in new way
A compound from the South African toothbrush tree inactivates a drug target for tuberculosis in a previously unseen way.
The compound under research, diospyrin (see below structure), binds to a novel site on a well-known enzyme, called DNA gyrase, and inactivates the enzyme. DNA gyrase is essential for bacteria and plants but is not present in animals or humans. It is established as an effective and safe drug target for antibiotics.
"The way that diospyrin works helps to explain why it is effective against drug-sensitive and drug-resistant strains of tuberculosis," said Professor Tony Maxwell from the John Innes Centre.
In traditional medicine the antibacterial properties of the tree are used for oral health and to treat medical complaints such bronchitis, pleurisy and venereal disease. Twigs from the tree are traditionally used as toothbrushes.
Most antibiotics originate from naturals sources, such as the soil bacteria Streptomyces. Antibiotics derived from plants are less common, but they are potentially rich sources of new medicines.
"Extracts from plants used in traditional medicine provide a source for novel compounds that may have antibacterial properties, which may then be developed as antibiotics," said Professor Maxwell.
Friday, January 18, 2013
Beta blocker use linked to NSCLC patient survival
Analysis shows that the 155 NSCLC patients given incidental beta blockers had significant better distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival than the 567 patients who were not given the agents.
However, beta blocker use had no impact on locoregional progression-free survival (LRPFS), leading the researchers to suggest that "the drugs may be affecting the tumor metastatic cascade rather than affecting the primary tumor."
The team investigated the impact of beta blockers on newly diagnosed NSCLC patients at the MD Anderson Cancer Center between 1998 and 2010 following reports that norepinephrine may stimulate tumor cell migration - a process could be targeted via the beta-adrenergic receptor.
Beta blocker use significantly predicted longer DMFS (hazard ratio [HR]=0.67), DFS (HR=0.74), and OS (HR=0.78), after adjusting for confounders including age, cancer stage, histology, tumor volume, Karnofsky performance score, use of concurrent chemotherapy, and radiation dose. Other factors including presence of hypertension or chronic obstructive pulmonary disease, and use of aspirin were also considered in the multivariate analysis.
The researchers note that 68% of patients were given beta blockers for hypertension. The remaining patients were given beta blockers for nonhypertensive disorders such as coronary heart disease.
Most patients were given selective (β1) beta blockers such as metoprolol (n=89)(left structure) and atenolol (above right structure)(n=43). Just 21 of the patients were given nonselective agents, such as carvedilol.
Thursday, January 17, 2013
Biguanide mechanism discovered
For fifty years, one of the few classes of therapeutics effective in reducing glucose production has been the biguanides, which include phenformin and metformin, the latter the most frequently prescribed drug for type-2 diabetes. Nonetheless, the mechanism of action of biguanides remains imperfectly understood. The suggestion a decade ago that metformin reduces glucose synthesis through activation of the enzyme AMP-activated protein kinase (AMPK) has recently been challenged by genetic loss-of-function experiments. Here we provide a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. In mouse hepatocytes, metformin leads to the accumulation of AMP and related nucleotides, which inhibit adenylate cyclase, reduce levels of cyclic AMP and protein kinase A (PKA) activity, abrogate phosphorylation of critical protein targets of PKA, and block glucagon-dependent glucose output from hepatocytes. These data support a mechanism of action for metformin involving antagonism of glucagon, and suggest an approach for the development of antidiabetic drugs....
Wednesday, January 16, 2013
Melanomas that develop resistance to vemurafenib also become addicted to the drug
In continuation of my update on vemurafenib
Researchers in California and Switzerland have discovered that melanomas that develop resistance to the anti-cancer drug vemurafenib (marketed as Zelboraf), also develop addiction to the drug, an observation that may have important implications for the lives of patients with late-stage disease.
The team, based at the University of California, San Francisco (UCSF), the Novartis Institutes for Biomedical Research (NIBR) in Emeryville, Calif., and University Hospital Zurich, found that one mechanism by which melanoma cells become resistant to vemurafenib also renders them "addicted" to the drug. As a result, the melanoma cells nefariously use vemurafenib to spur the growth of rapidly progressing, deadly and drug-resistant tumors.
Ref : http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11814.html
Tuesday, January 15, 2013
Results from Morphotek’s farletuzumab Phase III combination study on ovarian cancer
In continuation of my update on carboplatin and a taxane
Morphotek® Inc., a wholly-owned subsidiary of Eisai Inc., announced top-line results from a Phase III study of its investigational agent farletuzumab (MORAb-003) in combination with carboplatin and a taxane in patients with platinum-sensitive epithelial ovarian cancer in first relapse.
The study found that farletuzumab in combination with carboplatin and a taxane did not meet the study's primary endpoint of progression-free survival (PFS). The post hoc exploratory analysis showed, however, a trend toward improved PFS in some patient subsets and further analysis is ongoing.
The preliminary safety analysis indicated that the most commonly reported adverse events were those known to be associated with the study chemotherapy agents. Additionally, some immune-mediated events were observed with farletuzumab.
After further analysis of these clinical results, the company will determine a new development strategy based on discussion with external experts and relevant health authorities. In the double-blind, placebo-controlled study, 1,100 patients were enrolled to receive standard-of-care (carboplatin and a taxane [paclitaxel or docetaxel]) chemotherapy and were randomized to three parallel groups to receive one of two different dose levels of farletuzumab or placebo.
"While we are disappointed with these results, we know that ovarian cancer is a difficult disease to treat successfully," says Dr. Nicholas Nicolaides , President and CEO of Morphotek. "Morphotek remains committed to research to understand the potential role of farletuzumab in ovarian and other types of cancer."......
Monday, January 14, 2013
Melanomas that develop resistance to vemurafenib also become addicted to the drug
Vemurafenib (marketed as Zelboraf) is a B-Raf enzyme inhibitor developed by Plexxikon (now part of the Daiichi Sankyo group) and Hoffmann–La Roche for the treatment of late-stage melanoma. The name "vemurafenib" comes from V600E mutated BRAF inhibition.
Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011, Health Canada approval on February 15, 2012 and on February 20, 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer....
Mechanism : Vemurafenib has been shown to cause programmed cell death in melanoma cell lines. Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway if the B-Raf has the common V600E mutation.
Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.
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