New Results for PTC124 in Cystic Fibrosis

Cystic fibrosis (CF) is a hereditary disease characterised by the production of thick sticky mucus which results in frequent lung infections. CF is caused by any one of a number of mutations in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR) which encodes a protein that transports chloride ions across cell membranes. In about 10% of patients worldwide, and more than 50% of patients in Israel, CF is caused by nonsense mutations in the messenger RNA for CFTR. Premature stop codons prevent production of functional full-length protein: patients with nonsense-mutation CF produce very little functional CFTR and often have a severe form of CF.

New Phase II results published in The Lancet show that an orally bioavailable small molecule demonstrates activity in nonsense-mutation CF. PTC124 was designed to induce ribosomes to selectively read through premature stop codons to produce functional CFTR. The data show that treatment with PTC124 results in statistically significant improvements in the chloride channel function of patients.

Nonsense mutations account for a significant number of cases of most inherited diseases and PTC124 may have the potential to treat diseases other than CF.

Calpain Inhibitors in Models of Alzheimer’s Disease

Calpains are calcium-activated cysteine proteases which, when abnormally activated, can initiate degradation of proteins essential for neuronal survival. A report in Journal of Clinical Investigation describes the effect of the selective calpain inhibitor, BDA-410, in a transgenic mouse model of Alzheimer’s Disease.
Calpain inhibition by BDA-410 improved spatial-working memory and associative fear memory in APP/PS1 mice. The authors put forward a hypothesis in which amyloid peptides trigger a cascade leading to calpain activation and, ultimately, synaptic dysfunction and cognitive abnormalities. BDA-410 did not alter levels of amyloid oligomers or plaque load but restored normal phosphorylation levels of transcription factor CREB and normal distribution of synaptic protein, synapsin I. These results suggest that calpain inhibition might provide a new strategy for alleviating memory loss in Alzheimer’s Disease.

BDA-410 has previously been shown to be a potent inhibitor of cysteine proteases of the malaria parasite, Plasmodium falciparum.

Huntington’s Drug Approved in US

tetrabenazineHuntington’s Disease is a hereditary neurological disorder caused by a fault in the gene that produces a protein called Huntingtin.

The function of Huntingtin is not clear, but the presence of abnormal protein increases the rate of neuronal cell death and gives rise to physical, cognitive and psychiatric symptoms. Personality or mood changes may be the earliest signs of the disease, followed by uncontrollable jerky movements (chorea) and problems with memory. Although there is no cure for Huntington’s Disease, tetrabenazine (Xenazine®) has been shown to substantially reduce chorea. The drug is currently licensed for the treatment of Huntington’s Disease in a number of other countries, and has now been approved for use in the US.

Rheb is Overexpressed in Certain Cancers

The mTOR (mammalian target of rapamycin) pathway represents a convergence point for signalling pathways commonly disrupted in cancer. The pathway includes several known and putative oncogenes as well as tumour suppressors. Rheb GTPase is the upstream activator of the mTOR Complex 1 (mTORC1) and is itself activated by growth factors and nutrients.
Rheb crystal structure
Two independent papers in the August 15th issue of Genes and Development link Rheb activity with particular cancers. Wendel et. al. demonstrate that Rheb activation can produce rapid development of aggressive and drug-resistant lymphomas. The authors further show that activation of mTORC1 is dependent on farnesylation of Rheb and that an inhibitor of farnesyl transferase (FTI) is able to block the activation. It is noted that Rheb is highly expressed in certain human lymphomas.

Pandolfi et. al. show that overexpression of Rheb promotes hyperplasia and a low-grade neoplastic phenotype in the mouse prostate. Additionally, Rheb overexpression combined with Pten haploinsufficiency results in marked promotion of prostate tumorigenesis.

These results suggest potential for Rheb as a therapeutic target in particular oncology indications.

Cell Receptor for HCMV Entry Identified

Human Cytomegalovirus (HCMV) is a member of the Herpes virus family and infects 50-80% of adults in the US. After infection, the virus remains latent in the body for the rest of the person’s life. Most people who are infected with HCMV after birth remain asymptomatic unless their immune system is compromised by drugs (transplant recipients), HIV infection or old age. In such individuals, HCMV infections can become life-threatening.

The route by which the virus enters cells is not well understood, but a report in the journal Nature now shows that the HCMV glycoprotein B binds to cell-surface platelet-derived growth factor receptor-α(PDGFR-α), which acts as an entry receptor for HCMV. PDGFR-α is a receptor tyrosine kinase, and both laboratory and clinical strains of HCMV trigger autophosphorylation of the receptor, resulting in activation of downstream signalling pathways. Cells in which PDGFR-α was genetically deleted were non-permissive to HCMV entry, viral gene expression or infectious virus production. An HCMV glycoprotein B neutralizing antibody, an antibody to PDGRF-α and Gleevec, an inhibitor of the receptor kinase activity, also completely blocked viral entry. These data suggest that PDGFR-α is critical for HCMV infection and that the receptor provides a novel target for anti-HCMV therapies.
PDGFRs also play an important role in angiogenesis and have been linked to the pathogenesis of some tumors. Gleevec is marketed by Novartis for treating certain types of cancer.

MS Drug Could Also Fight Viral Infections

A drug that is being developed to treat multiple sclerosis (MS) by damping down the immune system may also have the potential to treat viral infections. A study published in the journal, Nature, showed that mice treated with the drug FTY-720 (fingolimod) were able to clear a viral meningitis infection that persisted in untreated mice.

It is, at first sight, surprising that a drug developed to suppress the immune response in MS patients can help to fight a viral infection.
FTY720-P is an agonist of the sphingosine-1-phosphate receptor and causes lymphopenia by preventing egress of lymphocytes from the lymph nodes. The new finding builds on the observation that more easily cleared strains of the virus also cause lymphocytes to become sequestered in lymph nodes. The reason why trapping circulating lymphocytes allows a more robust response to infection is not clear, but may be linked to the fact the lymph nodes are where the immune response is primed. Clearance of the virus does not occur when CD4 T cells are absent at the time of treatment, indicating that the drug is not exerting direct antiviral effects. Some viruses, including HIV, replicate at high levels in lymph nodes and the team plan to test the effect of FTY720 on infection with other viruses.

FTY720 is currently in Phase III clinical trials to test its safety and efficacy as a disease modifying therapy for relapsing-remitting MS.

Novel Mechanism of γ-Secretase Modulation

It is widely believed that reducing amyloid plaque formation will provide a disease-modifying treatment for Alzheimer’s Disease, either halting or slowing cognitive decline. Amyloid peptides, which aggregate to form neurotoxic plaques, are formed by proteolysis of a precursor protein by the action of two enzymes, β-secretase and γ-secretase. Inhibition of either of these proteases should prevent the formation of amyloid peptides, and much effort has been devoted to the identification of inhibitors. γ-Secretase, particularly, is a promiscuous enzyme and hydrolyses a number of other substrates, including Notch. The Notch signalling pathway is important in many cellular processes and so modulators rather than inhibitors of γ-secretase are preferred.

Amyloid pathway

Relatively early in the search for modulators of γ-secretase, the surprising discovery was made that certain nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, effectively suppress amyloid peptide production while sparing processing of Notch and other γ-secretase substrates. Further studies identified tarenflurbil (R-flurbiprofen, Flurizan, MPC-7869) as a γ-secretase modulator with the potential to treat Alzheimer’s Disease. A recent report in Nature (Kukar et. al., Nature 2008, 453, 925-929) has now shed new light on how such compounds prevent amyloid formation.


Using photoprobes, the group were able to show that flurbiprofen does not bind to the γ-secretase protein complex but, instead, binds to the amyloid precursor protein.

Disappointingly, Myriad Genetics have recently discontinued development of Flurizan since it failed in a phase III clinical trial in Alzheimer’s patients.

The study by Kukar et. al. does, however, suggest that it may be possible to identify other small molecules that reduce the formation of amyloid peptides by binding to the precursor protein rather than to the γ-secretase complex. It remains to be seen whether similar ‘substrate-binding’ inhibitors of other proteases can be identified.

Fitness without Effort?

AICARResearchers at the Salk Institute have shown that agonists of both AMP-activated protein kinase (AMPK ) and a peroxisome proliferator-activated receptor (PPAR) can mimic some of the beneficial effects of exercise in mice. In a treadmill running test, the PPAR-β/δ agonist, GW 1516 (GW 501516), acted synergistically with exercise to increase running endurance after 4 weeks. The AMPK agonist, AICAR, surprisingly enhanced running endurance even in sedentary mice, also after 4 weeks dosing. PPAR-δ and AMPK agonists have the potential to treat diseases such as diabetes, where exercise has been shown to be beneficial and to offer protection against obesity, but also have the more controversial potential to increase endurance in athletes.
Like exercise, AICAR and GW1516 trigger a variety of changes that contribute improved endurance and the ability of muscle cells to burn fat. A phase II clinical trial of GW1516 for the potential treatment of dyslipidemia has been completed.

New Approach to Treatment of Schizophrenia

Schizophrenia is a complex disorder, generally believed to arise from dysregulation of dopamine and glutamate neurotransmission pathways. Current front-line treatment comprises the atypical antipsychotics, which provide symptomatic relief but are associated with significant side-effects. These agents are broad-spectrum GPCR antagonists that act primarily at the dopamine and serotonin receptors.

Muscarinic acetylcholine (mACh) receptors regulate dopamine levels in areas of the brain associated with psychosis, with the M4 subtype speculated to be a key regulator of dopaminergic hyperactivity. The absence of subtype-selective modulators has, however, hindered validation of this hypothesis. Now scientists at Lilly have reported (PNAS, 5th August 2008) a selective small molecule, LY2033298, that targets the M4 subtype.

LY2033298The compound has been shown to act at an allosteric site on the receptor, potentiating agonist binding while having little effect on antagonist binding. The authors have further demonstrated in vivo activity in preclinical models that are predictive of antipsychotic drug effects.

New Life for Old Drug

Ore Pharmaceuticals has recently announced that it has acquired from Roche the exclusive development rights for the clinical-stage compound romazarit. Ore Pharmaceuticals specialises in identifying potential new uses for drug candidates that have previously failed clinical development for reasons other than safety.

RomazaritRomazarit was originally designed by scientists at Roche as a potential disease-modifying anti-rheumatic drug. The compound showed activity in an adjuvant arthritis model although the mechanism of action was not clearly defined. Romazarit was well tolerated in phase II clinical studies for rheumatoid arthritis, but did not make it to market.

Ore Pharmaceuticals has identified novel potential therapeutic uses for romazarit in prevalent metabolic diseases such as obesity, dyslipidemia and hypercholesterolaemia and has recently filed a patent application covering use of the compound for these indications. Romazarit has been shown to modulate a key pathway related to metabolic function, and lowered lipid levels, body weight, and plasma glucose levels in preclinical models. Ore Pharmaceuticals plans to select the most appropriate of the potential indications and prepare for Phase II clinical trials. The Company will engage in out-licensing efforts in parallel with internal development efforts.