Drug Discovery Opinion

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.

The 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.

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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.

Romazarit 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.

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Influenza A is a major human and animal pathogen with the ability to mutate and cross species: the recent emergence of the H5N1 strain of the Avian Influenza A virus has emphasised the need for new treatments. Between 2003 and 2008 there were 385 confirmed human cases of the avian H5N1 strain (WHO data).
Existing flu treatments such as Tamiflu^® and Relenza^® target the viral neuraminidase, a highly variable protein on the surface of the virus which can mutate to give viral strains which are resistant to the drugs.

PA-PB1 Complex (pdb id: 3cm8)

Two independent reports (He et.al., Obayashi et.al.) have recently described the crystal structure of the viral RNA polymerase, a protein complex that is essential for viral transcription and replication. The complex contains three proteins, PB1 which has polymerase and endonuclease activities, PB2 which is responsible for binding capped RNA, and PA, the function of which is less clear. Both structures show large fragments of PA bound to a smaller helical fragment of PB1. If it were possible to devise a small molecule that could disrupt this binding, it would likely prevent polymerase activity and viral replication. Although protein-protein interactions are considered to be difficult targets for drug discovery, in this case the binding area is relatively small and offers a potential target for novel anti-influenza drugs.

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Researchers at the University of Warwick have suggested that eating broccoli could undo the damage caused to heart blood vessels by diabetes. They found that sulforaphane, a compound found in broccoli, can prevent biochemical dysfunction induced by hyperglycemia in cultured endothelial cells. People with diabetes have a particularly high risk of heart disease and stroke, which are linked to damaged blood vessels.

Sulforaphane may also trigger production of thioredoxin, which protects against cell damage in the heart.

Studies have also linked consumption of cruciferous vegetables, such as broccoli, with decreased incidence of ischemic stroke.

It has also been reported that 3,3′-diindolylmethane and indole-3-carbinol, other compounds found in cruciferous vegetables, may have anticancer, antiviral, antibacterial and antioxidant properties.

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Rheumatoid Arthritis (RA) is a painful, chronic, progressive and disabling auto-immune disease. Newly released data has shown that a novel biologic, Actemra^™ (tocilizumab),  is superior to current standard of care in RA patients. Actemra^™ is a humanised monoclonal antibody to the interleukin-6 receptor that blocks the activity of interleukin-6, a protein that plays a major role in the RA inflammatory process. Actemra^™ is awaiting approval in the United States and Europe.  In Japan, Actemra^™ was approved for the treatment of RA in April 2008.

Other biologics are already used to treat RA and act at different points in the inflammatory process.

Orencia® (abatacept) works by reducing the activation of T-cells, which reduces the activation of other cells in the RA inflammatory process. Humera®(adalimumab), Enbrel®( etanercept) and Remicade® (infliximab) block the action of TNF-alpha, an inflammatory cytokine that leads to tissue damage. Mabthera® (rituximab) targets B cells, one of the key players in the pathogenesis of RA. Kineret® (anakinra) blocks the actions of the cytokine, IL-1.

The biologic medicines are usually prescribed together with the disease-modifying anti-rheumatic drug, methotrexate.

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AMD-3100

A drug which failed to reach the market as a treatment for HIV/AIDS has recently been shown to improve the survival of mice infected with West Nile virus, a virus that can cause encephalitis. It is believed that the drug, AMD-3100, acts by allowing T-cells to cross the blood-brain barrier and combat virus infecting the brain.

The drug works by blocking the receptor for the chemokine, CXCR4, and was originally developed to prevent the syncytium-forming variant of HIV using this receptor to gain entry to cells. Clinical trials, however, failed to show robust anti-viral activity.

The CXCR4 receptor and its physiological ligand, SDF-1, are also involved in mobilisation of hematopoietic stem cells into the bloodstream. Genzyme has recently filed applications in the US and Europe for AMD-3100 (Mozobil™, plerixafor) to enhance mobilization of hematopoietic stem cells for collection and subsequent autologous transplantation in patients with lymphoma and multiple myeloma. Because patients receive high-dose chemotherapy, which destroys bone marrow, a stem cell transplant is needed after chemotherapy to replenish blood-forming bone marrow cells. Genzyme has been developing Mozobil since its acquisition of AnorMED in 2006.

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There has been interest in the DNA polymerase sliding clamp as an antibacterial target for the last 15 years. Sliding clamp proteins, found in all organisms, encircle DNA (and slide along it!) and tether polymerases to enable rapid and processive DNA replication. The proteins are known as proliferating cell nuclear antigen (PCNA) in eukaryotes and as the β-clamp in prokaryotes. In PCNA the clamp is composed of three subunits of two domains each, whilst the bacterial β-clamp is assembled from two subunits of three domains. Although the overall structures of the eukaryotic and prokaryotic clamps are similar, there is no detectable sequence homology.

In a paper to be published in the August 12^th edition of PNAS, the authors disclose a small molecule inhibitor of the E.coli β-clamp, RU7, which differentially inhibits polymerases II, III and IV.

RU7 selectively inhibits Pol III in β-dependent replication assays, with no activity in the eukaryotic PCNA system. The compound, which has modest potency, was identified by screening for compounds able to displace a Pol III peptide from the β-clamp. The authors have also determined the co-crystal structure of RU7 bound to the clamp (pdb identifier 3d1g), paving the way for structure-based design.

PDB:3D1G

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Quark Pharmaceuticals has recently announced that its partner Pfizer has begun a phase II clinical trial of a chemically modified small interfering RNA (siRNA) molecule in patients with diabetic macular oedema. PF-4523655 inhibits abnormal blood vessel growth and leakage independently of the VEGF pathway, reduces inflammation and suppresses apoptosis. Results from a Phase I/II trial completed by Quark on Pfizer’s behalf showed that PF-4523655 was safe and well tolerated in patients with wet age-related macular degeneration who failed to respond to currently approved therapies. The new trial will test the safety and efficacy of PF-4523655 compared with laser surgery.

siRNA molecules interfere with the expression of specific genes and there is currently much interest in using the technology to treat a wide range of diseases, although there are several challenges that must be overcome if exogenous siRNA is to become widely used.

Despite the challenges, several siRNA molecules have entered clinical trials including TD101 for pachyonychia congenita (PC Project / TransDerm), Sirna-027/AGN-745 for age-related macular degeneration (Allergan), metastatic melanoma (Duke University), CALAA-01 for solid tumours (Calando Pharmaceuticals), Cand5 for diabetic macular oedema (Opko Health) and I5NP for acute kidney injury following cardiac bypass surgery (Quark Pharmaceuticals).

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A recent report in the journal Cell Metabolism (Cell Metab. 2008,7(5):377-388) identifies the serine/threonine kinase, calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), as a key component of the ghrelin signalling pathway. Ghrelin, which is produced in the stomach, is a polypeptide that promotes food intake by increasing production of the appetite-stimulating neurotransmitter, neuropeptide Y, by the hypothalamus. The authors established the role of CAMKK2 in appetite control and glucose tolerance both by experiments with CAMKK2-null mice and by administering the CAMKK2 inhibitor, STO-609, to normal mice. CAMKK2 is expressed at low levels in peripheral tissue and the effects of inhibition are likely to be brain-specific. The results suggest that blocking CAMKK2 has the potential to promote weight loss and improve glucose tolerance.

STO-609

Other approaches to the management of obesity targeting the ghrelin pathway are being investigated. A group at the Scripps Institute has developed an anti-obesity vaccine that is directed against ghrelin and a number of groups are investigating small molecule modulators of the ghrelin receptor.

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This week’s news has brought several stories that offer hope to Alzheimer’s patients and their carers. An experimental drug, Rember™, being developed by TauRx Therapeutics has been shown to slow progression of the disease. Rember™ is a new formulation of an old drug, methylene blue. The drug reduces the abnormal tangles of tau protein that are found in Alzheimer’s patients and thought to contribute to the disease. These tangles destroy neurons and their presence is strongly correlated with dementia. The company hopes to carry out further trials and, if these are successful, Rember™ could become available to patients in 2012.

Methylene Blue

Other researchers have also reported encouraging results for an experimental drug that targets tau tangles. AL-108 (Allon Therapeutics) is derived from an eight amino acid peptide (NAPVSIPQ: “NAP”) synthesized from a naturally occurring neuroprotective brain protein known as activity dependent neuroprotective protein (ADNP). The drug was tested in people with mild cognitive impairment and improved specific memory functions that are relevant in Alzheimer’s Disease.

In separate reports, angiotensin receptor antagonists and statins have both been linked with improved symptoms in Alzheimer’s patients.
Research suggests that people taking angiotensin receptor antagonists to treat hypertension are up to 45% less likely to develop Alzheimer’s Disease or dementia. The research was carried out by scientists at the Boston University School of Medicine and presented at the 2008 International Conference on Alzheimer’s Disease in Chicago. People taking the cholesterol lowering drugs known as statins for 5-7 years were also found to be at reduced risk of developing dementia according to a study published in the July issue of Neurology. (Neurology, Jul 2008; 71: 344 – 350)

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