Tuesday, October 16, 2012

ARIAD announces initial results from AP26113 Phase 1/2 trial on non-small cell lung cancer

We know that, AP26113 (see structure) is a highly potent ALK inhibitor with IC50 of 0.62 nM. As an ALK inhibitor, AP26113 overcomes mutation-based resistance in NSCLC models. Multiple mutations in ALK were identified that conferred resistance to crizotinib, but not AP26113, including the L1196M "gatekeeper" mutation which has now been observed clinically in patients who initially responded to crizotinib and then relapsed. AP26113 also inhibits activated EGFR in preclinical models, including the T790M "gatekeeper" mutant that confers resistance to current EGFR inhibitors. Constitutive EGFR activity due to activating mutation is a key feature of certain non-small cell lung cancers, and the T790M mutation causes resistance to inhibitor therapy in approximately 50 percent of these cases. In preclinical studies, AP26113 was shown to be specific for mutated EGFR and avoids inhibition of native (endogenous or unmutated) EGFR; such inhibition is thought to be associated with the toxicity of other EGFR inhibitors.

Sunday, October 14, 2012

Saturday, October 13, 2012

Beating Drug-Resistant TB.....


An antibiotic produced naturally by common soil bacteria kills Mycobacterium species that cause various human diseases, including tuberculosis (TB), according to a report published Monday (September 17) in EMBO Molecular Medicine. The antibiotic even kills drug-resistant strains that escape current TB treatments.
“I seldom get so tickled when I read a paper,” said William Jacobs, a microbiologist and immunologist at the Albert Einstein College of Medicine in New York, who did not participate in the research. The emergence of multidrug resistant strains of Mycobacterium tuberculosis “is a big problem,” he said. “This could be a godsend.”
Tuberculosis infections are commonly treated with a mixture of antibiotics, including one called isoniazid, which Jacobs described as “the cornerstone of TB therapy.”  Unfortunately, the most common drug-resistant strains of M. tuberculosis are isoniazid-resistant, he said.
Many researchers, including Stewart Cole, chair of the microbial pathogenesis department at the École Polytechnique Fédérale de Lausanne in Switzerland, have thus been searching for new M. tuberculosis-killing drugs. “In the past we’ve been working a lot on TB drug discovery using target-based approaches… [but] this has been spectacularly unsuccessful,” said Cole. So instead, he and his colleagues looked back over decades of academic literature searching for reports of natural compounds with M. tuberculosis-killing activity.
They found pyridomycin (see above structure). First described in the 1950s, the drug was reportedly produced by the bacteria Streptomyces pyridomyceticus and Dactylosporangium fulvum. Surprisingly, little was known about pyridomycin—perhaps, Cole suggested, because isoniazid was discovered around the same time and simply stole the limelight.
Cole’s team grew cultures of D. fulvum bacteria, figured out how to isolate and purify pyridomycin, and then showed that the drug was indeed capable of killing M. tuberculosis, as well as many otherMycobacterium species, in culture.
This indiscriminate Mycobacterium-killing ability is a bonus, said Cole. “One of the problems with isoniazid is that it only works against TB,” he said. “If pyridomycin makes it into the clinic, it could have applications in leprosy or Buruli ulcer or atypical mycobacterial infections that can occur in cystic fibrosis patients.”
The team went on to identify the bactericidal target of pyridomycin—a protein called inhA, which is involved in synthesis of bacterial cell wall components. As it happens, inhA is the same protein targeted by isoniazid, but there is a difference in the two drugs’ mechanisms. While isoniazid is a pro-drug that requires activation by an intracellular enzyme called KatG before it can bind to inhA, pyridomycin binds inhA directly.
This is an important distinction, explained Valerie Mizrahi, director of the Institute of Infectious Disease and Molecular Medicine at Cape Town University, South Africa, who was not involved in the study. The overwhelming majority of drug resistance mutations in M. tuberculosis occur in the KatGgene, she explained, and such mutant strains should not be resistant to pyridomycin. Indeed, the team showed that clinical isolates of isoniazid-resistant M. tuberculosis carrying KatG mutations were killed effectively by pyridomycin. “The efficacy against drug resistant forms of M. tuberculosis is particularly encouraging,” Mizrahi said.
There is, however, much to be done before pyridomycin can be used in the clinic. “We would [need to] test that it works in animal models and that it is safe and doesn’t have any side effects,” said Cole. “That will take a couple of years.”
“It’s a long journey,” agreed Mizrahi, “but the big plus is that they don’t really need to validate inhA as a drug target because inhA is already the most well validated drug target out there… [so] it has got a good head start.”

Ref : http://onlinelibrary.wiley.com/doi/10.1002/emmm.201201689/abstract

Friday, October 12, 2012

FDA approves Enzalutamide (XTANDI Capsules)



Enzalutamide (marketed as Xtandi and formerly known as MDV3100) is an androgen receptor antagonist drug developed by the pharmaceutical company Medivation for the treatment of castration-resistant prostate cancer  currently in phase 3 clinical trials. Medivation has reported up to an 89% decrease in prostate specific antigen serum levels after a month of taking the medicine. Early preclinical studies also suggest that enzalutamide inhibits breast cancer cell growth. In August of 2012, the U.S. Food and Drug Administration approved enzalutamide (see structure) for the treatment of castration-resistant prostate cancer......
 
Approved Drugs > Enzalutamide (XTANDI Capsules)

Thursday, October 11, 2012

GenSpera plans to initiate G-202 Phase II trial in prostate cancer


 We know that, a Mediterranean plant (see pic), Thapsia garganica, a simple weed, is the original source of G202. For millennia, the plant has been known to be poisonous to animals; in the days of desert caravans, it was called the “death carrot” for the unfortunate fate awaiting any camel that ingested it. Researchers at the Johns Hopkins Kimmel Cancer Center in the US and their Danish collaborators hoped to harness the toxicity of the plant in a controlled way that could be used to treat cancer in people.

They did so by taking apart the toxic compound, thapsigargin, produced by the plant and altering its chemical structure. The resulting prodrug, G202, is not active until it comes into contact with a particular protein produced by certain tumors. This prostate-specific membrane antigen (PMSA) is released by cells lining the outside of prostate and other tumors. Samuel Denmeade, the study’s lead author, uses the image of a hand grenade. The presence of PMSA essentially “pulls the pin” of the G202 grenade. In its active form, the drug is able to kill not only the tumor, but the blood vessels that provide it with nutrients.
A recent study of  G202,  looked at the effects of the drug on human prostate tumors grown in mice, and compared it to docetaxel, a chemotherapy drug already in use. G202 clearly came out on top, reducing by half the size of seven out of nine tumors; docetaxel achieved the same effect on only one out of eight tumors. Similar results for G202 were also seen in experiments with human breast, kidney and bladder cancer.

These promising results encouraged doctors to test the safety of G202 in a phase I clinical trial, involving 29 cancer patients at advanced stages of the disease.  

Now its  good news that,......


Tuesday, October 9, 2012

Potential new COPD drug

 
A study led by researchers at Boston University School of Medicine (BUSM) has shown that a compound used in some skin creams may halt the progression of emphysema and reverse some of the damage caused by the disease. When the compound Gly-His-Lys (GHK) was applied to lung cells from patients with emphysema, normal gene activity in altered cells was restored and damaged aspects of cellular function were repaired. 


Researchers took cells from lungs donated by patients undergoing a double lung transplant because their lungs were irrevocably damaged by COPD and found 127 genes had changes in activity as disease severity increased within the lung. The genes that showed increased activity included several that are associated with inflammation, such as those involved in signalling to B-cells (the immune system cells that make antibodies).

In contrast, the genes involved in maintaining cellular structure and normal cellular function, along with the growth factors TGFβ and VEGF, were down-regulated and showed decreased activity. Genes that control the ability of the cells to stick together (cell adhesion), produce the protein matrix that normally surrounds the cells and promote the normal association between lung cells and blood vessels were among the genes in this category. 

Using genomic technologies and computational methods, the researchers identified genetic activity defects that occur as emphysema progresses and matched these defects with compounds that could reverse the damage.


"Our study results showed that the way genes were affected by the compound GHK, a drug identified in the 1970s, was the complete opposite of the pattern we had seen in the cells damaged by emphysema," said Marc Lenburg, PhD, associate professor in computational biomedicine and bioinformatics at BUSM and one of the study's senior authors.

Potential new COPD drug

Monday, October 8, 2012

Potential drug for treatement of Alzheimer's disease investigated


Cannabinoid type 2 (CB2) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in Alzheimer's disease. We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine (MDA7 see below structure), a novel selective CB2 agonist that lacks psychoactivity—on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment induced by bilateral microinjection of amyloid-β (Aβ)1–40 fibrils into the hippocampal CA1 area of rats. In rats injected with Aβ1–40 fibrils, compared with the administration of intraperitoneal saline for 14 days, treatment with 15 mg/kg of intraperitoneal MDA7 daily for 14 days (1) ameliorated the expression of CD11b (microglia marker) and glial fibrillary acidic protein (astrocyte marker), (2) decreased the secretion of interleukin-1β, (3) decreased the upsurge of CB2 receptors, (4) promoted Aβ clearance, and (5) restored synaptic plasticity, cognition, and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for the treatment of Alzheimer's disease.




Potential drug for treatement of Alzheimer's disease investigated

Sunday, October 7, 2012

Carboranes Increase the Potency of Small Molecule Inhibitors of Nicotinamide Phosphoribosyltranferase - Journal of Medicinal Chemistry (ACS Publications)


We know that,  carborane is a cluster composed of boron and carbon atoms. Like many of the related boranes, these clusters are polyhedra and are similarly classified as closo-, nido-, arachno-, hypho-, etc. based on whether they represent a complete (closo-) polyhedron, or a polyhedron that is missing one (nido-), two (arachno-), or more vertices. Interesting examples of carboranes are the extremely stable icosahedral closo-carboranes.

A prominent example is the charge-neutral C2B10H12 or o-carborane with the prefix o derived from ortho, which has been explored for use in a wide range of applications from heat-resistant polymers to medical applications.  

Now researchers lead by Dr. Lee of University of Missouri used carboranes to build new drugs designed to shut off a cancer cell's energy production, which is vital for the cell's survival. All cells produce energy through complex, multi-step processes. The key to an effective drug is targeting the process that cancer cells depend on more than healthy cells. By increasing the binding strength of a drug, a smaller dose is required, minimizing side effects and increasing the effectiveness of the therapy. With carboranes, Lee found that the drug is able to bind 10 times more powerfully.

"The reason why these drugs bind stronger to their target is because carboranes exploit a unique and very strong form of hydrogen bonding, the strongest form of interactions for drugs," Lee said.

Lee said that this discovery also will lead to further uses for the drug.

"Too often, after radiation or chemotherapy, cancer cells repair themselves and reinvade the body," Lee said. "This drug not only selectively shuts off the energy production for the cancer cells, but it also inhibits the processes that allow those cancer cells to repair themselves. When we tested our carborane-based drugs, we found that they were unimaginably potent. So far, we have tested this on breast, lung and colon cancer, all with exceptional results."

According to Lee, this is the first study to show systematically how carboranes can improve the activity of a drug. Lee believes this discovery will open additional possibilities of improving drugs that are used to treat other diseases, not just cancer.

"The end result is that these new drugs could be many thousands of times more potent than the drugs that are used in the clinics today," Lee said.

 Carboranes Increase the Potency of Small Molecule Inhibitors of Nicotinamide Phosphoribosyltranferase - Journal of Medicinal Chemistry (ACS Publications)

Saturday, October 6, 2012

Thiabendazole drug slows tumor growth and shows promise as chemotherapy for cancer

An inexpensive antifungal drug, thiabendazole (see structure), slows tumor growth and shows promise as a chemotherapy for cancer. Scientists in the College of Natural Sciences at The University of Texas at Austin made this discovery by exploiting the evolutionary relatedness of yeast, frogs, mice and humans.



Thiabendazole is an FDA-approved, generic drug taken orally that has been in clinical use for 40 years as an antifungal. It is not currently used for cancer therapy.....


Friday, October 5, 2012

FDA Supports Phase 3 Trial for NGX-1998 | News | Drug Discovery and Development Magazine

NeurogesX Inc., a specialty pharmaceutical company focused on developing and commercializing a portfolio of novel non-opioid, pain management therapies, provided an update on its regulatory process for NGX-1998 (see below structure), the company's next generation liquid formulation of prescription-strength capsaicin. NeurogesX has received End-of-Phase 2 guidance from the U.S. Food and Drug Administration (FDA) regarding its previously announced plans for the Phase 3 clinical development of NGX-1998 as a treatment for neuropathic pain conditions, including key elements of its overall development plan related to manufacturing, applicator development, and clinical trial design.




FDA Supports Phase 3 Trial for NGX-1998 | News | Drug Discovery and Development Magazine

Thursday, October 4, 2012

Less commonly prescribed antibiotic may be better for bloodstream infections

 In continuation of my update on Vancomycin

Kevin Chan, MD (Fresenius Medical Care North America and Massachusetts General Hospital) and his colleagues compared the effectiveness of various antibiotics at preventing hospitalization and death from bloodstream infection. They reviewed more than 500,000 blood culture results from their chronic kidney disease database, looking for methicillin-sensitive strains of S. aureus bloodstream infection. They also identified when physicians used vancomycin or cefazolin to treat these infections. Vancomycin is often perceived as the better antibiotic because it has broad coverage against many strains of bacteria; however, other factors like the antibiotic's killing power and tissue penetration are also important factors in selecting the best treatment.


  
Among the major findings:
  • 56% of patients remained on vancomycin after blood culture results reported S. aureus bacteria were susceptible to cefazolin, while only 17% were treated with cefazolin. 
  • Cefazolin-treated patients experienced a 38% lower rate of hospitalization and death compared with vancomycin-treated patients. 
  • Cefazolin-treated patients also had a 48% lower rate of sepsis, which is the most serious form of bloodstream infection.
  • "I think the data suggest there is an opportunity to improve outcomes for patients through appropriate antibiotic selection," said Dr. Chan.

Ref : http://jasn.asnjournals.org/content/early/2012/08/15/ASN.2012010050

Wednesday, October 3, 2012

Resveratrol might help improve mobility and prevent life-threatening falls among older people

In continuation of my update on Resveratrol...

"Our study suggests that a natural compound like resveratrol, which can be obtained either through dietary supplementation or diet itself, could actually decrease some of the motor deficiencies that are seen in our aging population," said Jane E. Cavanaugh, Ph.D., leader of the research team. "And that would, therefore, increase an aging person's quality of life and decrease their risk of hospitalization due to slips and falls."

Tuesday, October 2, 2012

FDA Approves Stivarga | News | Drug Discovery and Development Magazine

Golden age of prostate cancer treatment hailed as fourth drug in two years extends life

We know that, Enzalutamide (formerly known as MDV3100, see the structure) is an experimental androgen receptor antagonist drug developed by the pharmaceutical company Medication for the treatment of castration-resistant prostate cancer currently in phase 3 clinical trials. Results so far have been encouraging; Medivation has reported up to an 89% decrease in prostate specific antigen serum levels after a month of taking the medicine. Early preclinical studies also suggest that enzalutamide inhibits breast cancer cell growth. 

Researchers from Institute of Cancer Research, London, and its partner hospital The Royal Marsden NHS Foundation Trust jointly led the new Phase III trial of enzalutamide and the Phase III trials of two other drugs, cabazitaxel and abiraterone. Abiraterone was also discovered at The Institute of Cancer Research and was recently made available on the NHS. A further drug sipuleucel-T has also been shown to extend life in the two-year period.

"What we're seeing now is an unprecedented period of success for prostate cancer research, with four new drugs shown to extend life in major clinical trials in just two years, and several others showing promise. It truly is a golden age for prostate cancer drug discovery and development" claims Prof. Martin Gore....

Monday, October 1, 2012

AEOL10150 Protects Against Nerve Gas | News | Drug Discovery and Development Magazine

The study confirmed AEOL10150 (see structure)’s ability to cross the rat blood brain barrier and achieve sufficient levels to exert its neuroprotective effects.  Further, the study showed that subcutaneous administration of AEOL10150 30 min prior to or 60 and 90 minutes after nerve agent exposure resulted in inhibition of markers of oxidative stress and neuronal damage.

“These new data show that AEOL 10150 has potential neuroprotective properties against chemical nerve agents and broaden the utility of protection proved by AEOL 10150 across the chemical threat spectrum”, stated John L. McManus, President and Chief Executive Officer of Aeolus Pharmaceuticals, Inc.  “This study builds on prior work that has shown AEOL 10150 to be an effective countermeasure to protect the lungs from damage due to inhalation of chlorine, sulfur mustard, and phosgene gas and well as protection against radiologic damage to the lungs and gastrointestinal tract.”  

AEOL10150 Protects Against Nerve Gas | News | Drug Discovery and Development Magazine