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Feature

Emerging Drug Discovery Targets

22 April 2003 Posted on: 20 Apr 03

Summary

TherapeuticAdvances: 27th February 2003

 

Emerging Drug Discovery Targets

from LeadDiscovery

22 April 2003

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In this weeks edition:

  • Optimizing oncolytic viruses [more]
  • Retinoids as a target for the treatment of Alzheimer's disease (license opportunity) [more]
  • Nitric oxide synthase and NMDA receptors as targets for osteoporosis [more]
  • Advances from industry [more]
  • Today's breaking scientific publications for the drug development community [more]
  • This week's licensing opportunities [more]
    • Potent PDE4 inhibitors
    • Retinoids as candidate targets for alzheimer’s disease treatment
    • Novel therapeutic targets for prostate cancer
    • New treatment options for ischemia reperfusion injury
    • A series of novel kinases as new targets for colorectal cancer
  • New DiscoveryDossiers [more]:
    • Therapeutic & pharmaceutical opportunities for osteoporosis and atherosclerosis
    • The lymphoma market: Keeping up in a fragmented and competitive environment

"Emerging Drug Discovery Targets" provides a summary of some of the most exciting breaking data featured in LeadDiscovery's TherapeuticAdvances service. Readers can log-on to this service free of charge at http://www.leaddiscovery.co.uk/TherapeuticAdvances%20Archive/110403/index.html

Please feel free to distribute "Emerging Drug Discovery Targets" to your colleagues or arrange for it to be accessed through your company intranet.


Optimizing oncolytic viruses: Cancer continues to drive the identification and development of new therapeutic strategies. LeadDiscovery has focussed on a number of these over recent months. Particularly exciting are the endogenous inhibitors of apoptosis (click here for more); histone deacetylase inhibitors (access our recent dossier on this field here); and the retinoids (click here for more). Oncolytic viruses represent a further approach to cancer with considerable potential. Although the cytotoxic effects of viruses are usually viewed in terms of pathogenicity, it is possible to harness this activity for therapeutic purposes. In particular, viral genomes are highly versatile, and can be modified to direct their cytotoxicity towards cancer cells. To our knowledge there are almost 20 such oncolytic virus-based therapeutics in development by the pharma/biotech sector. Although most of these are in preclinical development, therapies form Cell Genesys, Crusade, Medigene and Oncolytics are in phase II trial.

Human adenovirus serotype 5 (Ad5) represents a particularly attractive family of oncolytic candidates, showing good efficacy and selectivity for tumor cells. These virus vectors have been modified to replicate preferentially in tumor cells; their oncolytic activity being a natural consequence of the lytic life cycle of Ad5. Field-leaders at the Saint Louis University School of Medicine previously reported on two Ad vectors, KD1 and KD3 that carry two small deletions in the Ad E1A gene. These mutations restrict the replication of KD1 and KD3 to cells with a deregulated cell cycle. These vectors also overexpress the ADP protein, also named E3-11.6K. ADP is an Ad5 protein that facilitates the lysis of the infected cell and the egress of virus from these cells. The Saint Louis group has shown that vectors that overexpress ADP spread from cell-to-cell faster than wild-type Ad5, and that this enhanced vector spread results in improved oncolytic properties of the vector. In addition to the E1A mutations and enhanced ADP expression, in KD1 and KD3 the E3 genes responsible for the down-modulation of the host immune response are deleted. This latter feature decreases the possibility of runaway vector replication. KD1 and KD3 have performed very well in tissue culture as well as in tumor xenotransplant experiments. They obstructed the growth of pre-established subcutaneous human tumor xenografts in nude mice to a level comparable to treatment with wild-type Ad5.

A review of the literature suggested that in in vitro experiments and especially in a clinical setting, the oncolytic effect of tumor-selective replicating Ads can be augmented by the use of concomitant radiation and/or chemotherapy. Following this reasoning, the Saint Louis group tested if the combination of ADP-overexpressing Ad vectors with radiation therapy increased the potency of the vectors. In in vitro experiments, radiation was shown to enhance the ability of KD1 and KD3 to kill tumor cells by a factor of ten to a hundred. In the nude mouse-human tumor xenograft model, KD3 or radiation alone reduced tumor growth by about 5-fold. Combining these two approaches further improved this effect reducing tumor growth by 20-fold. Oncologists and radiation oncologists have been applying a combination of different modalities that allows for lower doses of individual components, thereby reducing the side effects of radiation and chemotherapy while maintaining the efficacy of the treatment. These data therefore suggest that KD3 represents a means of alleviating the side effects associated with using high-dose single-modality anti-cancer treatments.
[more on these findings]

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Retinoids as a target for the treatment of Alzheimer's disease:  Four million Americans currently suffer from Alzheimer's disease (AD), and experts estimate that 22 million people around the world will be so afflicted by 2025. Acetylcholinestase inhibitors dominate the current AD market driving value of this therapeutic class to over US$1.2 billion in 2001. Although current AD treatments center on treating symptoms, future strategies are more likely to modify the course of the disease. The most widely accepted hypothesis on the etiopathogenesis of AD proposes that aggregates of the amyloid protein, trigger tau hyperphosphorylation and neural degeneration. Neurotoxicity is thought to be due to altered calcium regulation, mitochondrial damage and/or immune stimulation.

The retinoids play a key role in differentiation, proliferation and apoptosis and as a result over 30 naturally occurring and synthetic analogs of retinoic acid are now either in development or on the market. The focus of retinoid attention has been skin conditions and cancer, however although efficacy has been demonstrated in acute promyelocytic leukemia and various skin cancers, the extension of therapeutic benefit to other diseases has been limited. In our recent dossier "Retinoids: An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development" (click here for access) we set out to offer a full and up to date insight into the complexities of the retinoids. Furthermore we describe how these complexities relate to the limited therapeutic potential of the retinoids and strategies for overcoming these limitations.

As our understanding of the retinoids increases so do their therapeutic indications. For example COPD and obesity have both recently emerged as targets for retinoic acid receptor ligands. Most recently Boston based researchers have put forward the hypothesis that late onset AD is influenced by the availability in brain of retinoic acid. This hypothesis is based on a body of genetic, metabolic, and environmental/dietary evidence. For example, significant genetic linkages to AD are demonstrated for markers close to four of the six retinoic acid receptors; three of the four retinol-binding proteins and the retinoic acid-degrading cytochrome P450 enzymes (for further information on each of these proteins and retinoid pathways go to our retinoid dossier). Retinaldehyde dehydrogenase (RLDH), the enzyme that forms retinoic acid from retinaldehyde, was present in hippocampus, frontal cortex, and parietal cortex, and its activity in the hippocampus and parietal cortex of Alzheimer diseased brains was 1.5- to 2-fold higher compared to controls. In contrast, the RLDH activity of frontal cortex was the same for both Alzheimer diseased and control groups.

Retinoid responsive transgenes have been shown to be highly active in the hippocampus and the activation of such genes has been reported to facilitate neurotrophin-induced maturation of stem cells into neurons. While retinoic acid may be important in neurogenesis, defects in the retinoid pathway may lead to impaired neurological function. This is supported by data showing that retinoid receptor expression is reduced in aged mice and that this is related to behavioral deficits consistent with diminished cognitive function. This could be reversed by retinoic acid treatment. This and the genetic/molecular evidence linking the retinoids to Alzheimer’s disease suggests that retinoic acid or its mimics may represent a useful approach to the treatment of cognitive disorders. Of particular interest to the treatment of Alzheimer’s disease it has been shown that the reductions in acetylcholine content caused by Abeta42 could be prevented by a co-treatment with retinoic acid.

On the other hand however, evidence is also available to suggest that retinoic acid can increase secreted Abeta40 and Abeta42. Of interest the response was biased towards the latter, more cytotoxic form of beta amyloid. Careful drug design could therefore conceivably lead to the development of a treatment that both improves cognition and also limits the suggested underlying cause of Alzheimer’s disease.

With the advent of improved models of Alzheimer's disease as well as a greater inventory of pharmacological tools able to probe retinoid biology, further studies designed to probe this provocative link between the retinoids and AD are eagerly awaited.
[more on these findings]

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Nitric oxide synthase and NMDA receptors as targets for osteoporosis: An estimated 10 million Americans over the age of 50 years old suffer from osteoporosis and a further 32.9 million have low bone mass, placing them at an increased risk for developing this condition. Associated with an increased risk of fractures, which are both clinically problematic and costly to healthcare systems. The development of new osteoporosis treatments therefore offers immense opportunities to the pharmaceutical industry. The global osteoporosis therapies market, including estrogen replacement therapy drugs was estimated at $5.5 billion in 2001 and projected to double by 2008 in the face of population aging, decreased bone quality and increased awareness of osteoporosis.

Once dominated by hormone replacement therapies (HRTs), the field of osteoporosis has undergone three major changes since the mid-1990's. First, the bisphosphonate Fosamax was launched in 1995. Since this launch the bisphosphonates have become the most effective means of limiting bone loss. Then, in January 1998 Eli Lilly launched Evista (raloxifene), the first selective estrogen receptor modulator and as a result the concept of combining the beneficial effects of estrogen antagonism (ie anti-cancer activity) and agonism (ie bone health) became a real therapeutic possibility. Most recently the FDA has approved the use of the parathyroid hormone Forteo (teriparatide), the first treatment for osteoporosis with anabolic activity. In a recent DiscoveryDossier we analyze therapeutic and pharmaceutical opportunities in the field of osteoporosis (click here for access).

Nitric oxide has been shown to play an important role in the regulation of bone resorption. However, the role of endogenous nitric oxide (NO) on osteoclast activity remains controversial. Researchers at the Universite de Picardie-Jules Verne in France have recently demonstrated that rabbit mature osteoclasts express mRNA encoding for neuronal NO synthase (nNOS) suggesting that this enzyme could be involved in basal NO production in these cells. Further study revealed that a NO scavenger inhibited osteoclastic bone resorption in a dose dependent manner and induced osteoclast apoptosis by a mechanism involving caspase 3 activation. These results suggest that basal concentration of endogenous NO may be essential for normal bone resorption by supporting osteoclast survival.

In a further series of experiments the specific non-competitive NMDA receptor antagonists, MK801 and DEP, were shown to strongly inhibit bone resorption. As with the NO scavenger, this was related to osteoclast apoptosis and caspase 3 activation. Since MK801-induced osteoclast apoptosis was partially reversed in the presence of small amount of the NO donor, SNAP, and because the NMDA receptor is involved in NO production in neuronal cells, it is hypothesized that the activation of osteoclast NMDA receptors could have a similar function as those in neuronal cells.

These studies confirm the role of NO in bone resorption and suggest that NO scavengers or preventing the generation of NO by inhibiting nNOS or through the use of NMDA antagonists represents a new approach to the serious problem of osteoporosis.
[more on these findings]

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Advances from industry

  • NW-1029: Newron’s Na(+) channel inhibitor, NW-1029, has recentl;y been shown to reduce hyperalgesia in both inflammatory and the neuropathic pain models at doses below 1mg/kg (po). No effects were observed in the hot-plate and tail-flick tests of acute pain up to 30 mg/kg p.o. The compound orally administered was well tolerated, without signs of neurological impairment up to high doses. NW-1029 has recently entered into phase I evaluation.
  • Aprepitant: The US FDA has approved Merck & Co’s aprepitant (EMEND) for use in combination with other anti-emesis and anti-vomiting agents for the prevention of acute and delayed nausea and vomiting induced by chemotherapy. Aprepitant is an NK1 antagonist and phase III trials are also being conducted using the agent for the treatment of depression.
  • Adefovir dipivoxil: Gilead Sciences’ reverse transcriptase inhibitor, adefovir dipivoxil (HEPSERA), has been launched in the UK. This nucleotide analogue is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with: compensated liver disease with evidence of active viral replication; persistently elevated serum alanine aminotransferase levels and histological evidence of active liver inflammation and fibrosis; or decompensated liver disease.

New DiscoveryDossiers:

  • Therapeutic & pharmaceutical opportunities for osteoporosis and atherosclerosis [More]
  • The lymphoma market: Keeping up in a fragmented and competitive environment [More]

LeadDiscovery

Last updated on: 27/08/2010 11:40:18

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