Hope for Drug to Reduce Old-Age-Related Muscle Wasting

Guest Post – Lily Bryant

The results of a study carried out by researchers at the Center of Regenerative Medicine at Massachusetts General Hospital in Boston, USA, and the Department of Craniofacial Development and Stem Cell Biology at King’s College London, England, indicate that a cure for muscle weakening caused by old age might be on the horizon. Muscle wasting is an inevitable symptom of growing older. It can be slowed down by regularly exercising but there is no known way of reversing it at the moment. This looks set to change though, as the researchers have treated old mice with a drug that has significantly improved the ability of their aged muscle tissue to self-repair. 

Fibroblast Growth Factor 2 

Strenuous activity, such as doing press-ups or lifting weights, results in a small level of damage to the muscles. Stem cells are triggered to repair them by dividing and developing into new muscle fibers. This results in big arms and rippling torsos. However, weakening of the muscles due to old age means that bulging biceps can soon become puny and weak. This occurs because as people grow older, their muscle loses its ability to regenerate. A study conducted by the University of Potsdam in Germany indicates that people lose just under a third of their muscle strength between the ages of fifty and seventy. The researchers at Massachusetts General Hospital and King’s College London deduced that this is due to the fact that the number of dormant stem cells in muscles decreases with age. They concluded that in mice, this was caused by excessively high levels of a protein that stimulates cells to divide, known as fibroblast growth factor 2 (FGF2). 

Preventing Muscle Stem Cell Decline 

In aging muscle, fibroblast growth factor 2 was found to be continuously awakening dormant stem cells for no reason. The stem cell supply was observed to deplete over time, meaning that an insufficient number were available when they were really needed. As a result of this, muscle regeneration ability was impaired. The researchers discovered that using a drug called SU5402 that inhibits fibroblast growth factor 2 can prevent muscle stem cell decline in aging mice. Treating the elderly rodents with this drug increased their ability to repair muscle tissue. 

Reducing the Impact of Old Age 

Dr Albert Basson, who is a senior researcher at King’s College London, has stated that the findings mean that treatments that could make old muscles young again could one day be developed, thus reducing the impact of old age. He says that if such a treatment came into existence, people would be able to live more independent, mobile lives as they grew older. Senior author Dr Andrew Brack of Massachusetts General Hospital says that just as it is important for athletes to schedule recovery into the time that is taken for training, stem cells require time in which to recuperate but elderly cells recuperate less often. Scientists are yet to figure out why it is that levels of fibroblast growth factor 2 increase causing excessive stem cell activation as people get older. Research team member Kieran Jones of King’s College London says that the next step is to conduct an analysis of old muscle in humans in order to see whether or not the same mechanism is responsible for the depletion of stem cells in human muscle fibers leading to wasting and loss of mass. 

The Implications of the Research 

Once it has been confirmed that stem cells in human muscle fibers are negatively affected by fibroblast growth factor 2, work can start on introducing a drug to the market that will stop the process from taking place and consequently reduce the extent to which elderly people are immobilized and prevented from doing what they want to do by the effects of age-related muscle weakening. The average life expectancy in India has increased by over four and a half years since 1998. Now that people are living longer than they used to live for, a drug that reduces the amount to which becoming elderly negatively impacts upon the quality people’s lives would be extremely beneficial. It would mean that individuals who have reached the later stages of their lives could enjoy the time that they have left without having their independence limited by their muscles becoming increasingly weak and feeble.

About Lily Bryant

Lily Bryant is a writer working with one of only two licensed online pharmacies in the US. She is strongly interested in promoting and creating content aimed at relevant readers as part of her role in ethical healthcare business. She believes that it is important that we play a strong role in leading society towards a healthier lifestyle through the promotion of exercise and healthy diet rather than an early adoption of drug treatment.

Modulators of Protein–Protein Interactions

Protein-protein interactions (PPI) play a crucial role in most biological processes. This nature of PPI has put forward itself as a prospective candidate for therapeutic intervention. Traditional small molecule target classes such as Enzymes, GPCRs, Kinases, etc. have a deep pocket (often used to bind an endogenous substrate), where small molecules tend to bind. On the other hand, PPIs appear to be too large and featureless for small molecules to bind against. Hence, due to this lack of well-defined binding pockets, they were considered unsuitable/ extremely hard for targeting small molecules. 

Attempts at generating small molecule modulators of PPIs have been largely unsuccessful by adopting existing chemical techniques. This leads us to believe that we need to identify novel chemical space that can leverage the flat and expansive surfaces of PPI, which would in turn provide an effective binding for small molecules. However, pharmaceutical companies are rather unwilling to add compounds containing multiple rings, multiple stereocenters that are highly complex, into their corporate collection as it does not align with their immediate short-term business goals.

Heterocyclic compounds (aromatic, largely flat and hydrophobic)

+

Natural products (rich in sp2 bonds)

=

Natural Product Inspired   (New Chemical toolbox)

Dr. Prabhat Arya is developing a new chemical toolbox enriched with both Heterocyclic Compounds and Natural Products to tackle such issues from Dr. Reddy’s Institute of Life Sciences. This approach could create a large 3D surface area, numerous binding interactions, rich stereochemical diversity, which would, in turn, solve the poor cell permeability of natural products, not to mention the added advantage of overcrowded IP Space.

The field of small-molecule-PP interactions appears to be highly promising, and in the near future, we can hope to see several strategies and techniques that will pave the way towards discovering novel agents in this regard.

Kinase Inhibitors: beyond Oncology

We recently published a paper in Bioorganic and Medicinal Chemistry, targeting Interleukin-2 inducible T-cell kinase (ITK) for treating Asthma. 

Protein kinases are prime targets for anticancer therapies, but achieving specificity for a particular kinase is challenging because of their close structural similarities. This leads to unwanted side effects, and the toxic outcome may also be due to the result of tissue distribution of kinase inhibitors. Imatinib has been highly successful in treating both chronic myelogenous leukemia, gastrointestinal stromal tumors, and other cancers but is associated with severe cardiotoxicity. Toxicity may be of less concern with oncologic kinases; what about non-cancer indications? Emerging clinical evidence (Nature Drug Discovery) of oral kinase inhibitors other than cancer shows that kinases could effectively inhibit the number of inflammatory pathways.

Almost all the p38MAPK inhibitors having hepatotoxicity issue. For example, SCIO 469 and Arry 797 initially developed for RA but went into the clinic for post operative dental pain; here, the potential toxicity problems will not show up because the drugs are used only for a very short time. Are BMS-582949 and VX 702 still in development? Different companies have spent hundreds of millions on P38 with nothing to show at the end.

Tasocitinib may be the first kinase inhibitor (JAK3) for non-oncology indication and the first oral DMARD for RA in a decade if it successfully completes Phase III clinical trials.

GABA receptors as RA and Pain Targets? The Missing Link

Kelley et al. proposed a hypothesis for an inefficient GABA signaling system that resulted in unchecked pro-inflammatory cytokine production via the p38 MAP kinase pathway. p38 is a kinase target that regulates the production of inflammatory cytokines TNF, IL-1, IL-6, and PGE2. TNF, IL-1, and IL-6 are well-validated cytokines for controlling inflammation in rheumatoid arthritis (RA), and PGE2 is an essential mediator for inflammatory pain. However, most of the p38 projects failed to deliver drugs due to CNS toxicity. Are these CNS side effects linked to GABA? 

The research team led by Ulrich Zeilhofer used genetically altered mice in experiments to target the GABA receptors that control spinal pain relay. They showed that the non-sedative benzodiazepine ligand L- 838417 (a GABA receptor ligand) is highly effective against inflammatory and neuropathic pain. Clomethiazole edisilate is a drug that acts on GABA receptor, which inhibits the p38 MAPK too. This small molecule does not have other p38 inhibitors' structural features, which seems to support this hypothesis. The task is to find which subtype of GABA responsible for the chronic pain. However, no direct link has been reported between GABA and p38 MAPK. The role of GABA in RA and pain development will encourage further integration of Immunology in clinical neuroscience. These findings may provide a rational basis for developing subtype-selective GABAergic drugs to treat RA and chronic pain.

Are Protein Kinases Drug Targets?

Kinases catalyze the transfer of phosphate groups from phosphate-donating molecules (like ATP) to other molecules. They have been intensively investigated as drug targets for many years. Around 20-25% of the druggable genome consists of kinases, and this target accounts for 20-30% of many companies' drug discovery programs.

Several protein kinase inhibitors have been approved by FDA and available in the market which includes Tykerb®, Sprycel®, Sutent®, Nexavar®, Tarceva®, Iressa®, and Gleevec®. Many other kinase inhibitors are currently undergoing clinical development. This accelerated the research and development in this area, reflecting the number of search results for 'kinase inhibitors'. Sci-finder keyword search resulted in 1281 patents, which is filed in 2007 alone. Drug and Market Development’s (D&MD) report (2005) shows that kinase targeted therapies growing from $12.7 billion in 2005 to $58.6 billion in 2010. 

 

So what is the problem with kinases? The lack of selectivity for targeting a specific kinase is the issue due to the similarity of other kinase targets. For example, the natural product substrate Staurosporine hits almost every kinase out there will be gratuitously toxic. However, the real problem with kinase inhibitors is the toxic outcomes may result from tissue distribution of orally administered kinase inhibitors.

 

Kinases are drug targets. But, difficult ones.

The making of hERG free molecules (The Role of Fluorine)

The unwanted hERG affinity could be removed by moderating 

1) basicity (control pka),

2) lipophilicity of the compound, and 

3) steric environment of the central nitrogen 

A paper in BMCL from Pfizer reported the pka, lipophilicity, independent optimization of hERG affinity for the CCR5 antagonist ‘Maraviroc’. The steric demand and the dipole generated by the difluoro moiety of 4 4’difluoro cyclohexyl group in maraviroc are clearly not tolerated within the hERG channel.

 

Overcoming hERG affinity in kinesin spindle protein inhibitor MK-0731 for the treatment of Taxane Refractory Cancer was achieved by making axial fluorine in the piperidine ring.

The Histamine H4 Receptor: Drug Discovery in the Post-genomic Era

The Histamine H4R receptor is the most recently identified G-protein coupled receptor, with little homology to the classical pro-inflammatory histamine H1 or the histamine H2 receptor, and some 35% homology with H3 receptor.

 The high expression of the histamine H4 receptor in cells of hemopoietic lineage and immune cells suggests that this new histamine receptor plays a role in inflammatory and immune responses. Activation of the Histamine receptor can mediate calcium mobilization and chemotaxis in mast cells.

Preliminary studies on the H4R and specific antagonist (JNJ 7777120 - Johnson & Johnson, VUF6002-Janssen Pharma.) suggest another rich vein of histamine receptors therapeutics, likely to generate more blockbusters and medical breakthroughs, could be on the horizon.

Ref: Nature Reviews Drug Discovery, 7, 41-53, 2008, Trends Pharmacol. Sci. 26, 462-469, 2005.