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Feature

TherapeuticAdvances: 14th November, 2002

Posted on: 20 Nov 02

Summary

This week’s TherapeuticAdvances focuses on histone deacetylase inhibitors; in particular their use as antifungal as well as anti-metastatic agents. We also feature compelling data supporting the use o
November 14th

LeadDiscovery.co.uk is a company founded by industrial researchers for the drug development sector. Our panel of pharmaceutical scientists produces TherapeuticAdvances, a twice-monthly bulletin of cutting edge scientific research with therapeutic potential. Selected research is fully analyzed in DiscoveryDossiers. These dossiers can be produced for institutions as due diligence reports or to boost technology transfer/partnering activity. Alternatively, dossiers can be purchased as overviews to support target identification or development efforts.

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An overview of TherapeuticAdvances

14th November 2002

Free log-on at http://www.leaddiscovery.co.uk/TherapeuticAdvances%20Archive/141102/index.html

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This week’s TherapeuticAdvances focuses on histone deacetylase inhibitors; in particular their use as antifungal as well as anti-metastatic agents. We also feature compelling data supporting the use of microplasmin, a licensing opportunity from ThromboGenics as a treatment of stroke. Finally, we highlight two new therapeutic candidates, CD200Fc as a treatment of autoimmune disease and TLK19780, an insulin receptor modulator, as a treatment of metabolic disease.

In this weeks edition:

  • Broadening indications for histone deacetylase inhibitors [more]
  • New treatments for stroke  [more]
  • Advances in the treatment of autoimmune disease [more]
  • Therapeutic activity of a new kinase modulator [more]

NEW: Please note that on 14th November, LeadDiscovery launched the fully redesigned DailyUpdates service. This free applet is the first ever "newsfeed" service that delivers breaking scientific publications selected for their drug development importance. This service can be accessed at our log-on page or webmasters can download it onto company intranets or websites.

Broadening indications for histone deacetylase inhibitors

The field of histone deacetylation represents one of the most recent therapeutic targets to fall under the oncology spotlight. As a result, information relating to histone deacetylases (HDACs) is emerging with breathtaking rapidity with over 1 new article currently being published every day. LeadDiscovery has recently responded to this activity by publishing one of the most comprehensive overviews of the pharmaceutical potential of the histone deacetylase (HDAC) inhibitors to date (click here to access). This report focuses on the involvement of HDACs in multiple aspects of tumor progression including cell cycling, differentiation and proliferation, angiogenesis and apoptosis. A further component of tumor progression is extracellular matrix degradation, which contributes to both metastasis and angiogenesis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases collectively capable of degrading essentially all matrix components. Over 20 MMP modulating agents are in pharmaceutical development, almost half of which are indicated for cancer. The "Focus on Oncology" section of the current edition of TherapeuticAdvances highlights research which shows that HDAC inhibitors decrease expression and activity of gelatinase A (MMP2; Type IV collagenase). This matrix metalloproteinase is implicated in tumorigenesis and metastasis therefore strengthening the rationale for developing HDAC inhibitors as anti-cancer agents.

As a natural consequence of the weight of data emerging in relation to HDACs, numerous indications in addition to cancer are emerging for inhibitors of these enzymes. In the current edition of TherapeuticAdvances we focus on infectious disease as an indication for HDAC inhibitors. Like the HDACs, infectious diseases have recently attracted considerable attention on the LeadDiscovery website. This is because the anti-infectives market is poised to experience considerable growth in the next few years, with a forecast market value that is expected to double in size to more than $44 billion by 2010. This whole area is overviewed in one of our recently featured reports "Anti-Infectives 2002" (click here for access). One particularly unmet area of this therapeutic field is fungal infection and especially candidiasis, a common and costly hospital-acquired infections (for reviews click here for "The Next Generation Antifungals: Triazoles vs. Peptides" or here for "New Targets and Drug Discovery Platforms in Antifungal R&D"). The current edition of TherapeuticAdvances highlights research demonstrating that HDAC inhibitors increase the sensitivity of various species of Candida to commonly used anti-fungals [for further details of these and other projects log on to TherapeuticAdvances]

New treatments for stroke 

The treatment of ischemic stroke remains one of the most challenging areas of medicine today. At present, only one agent is approved (Alteplase, rt-PA). However, since symptomatic and fatal hemorrhage is more common in patients receiving t-PA than in those receiving placebo, it has been recommended that thrombolytics be used for only a brief window of time (onset of symptoms less than three hours) and only in the event that emergency back-up resources are available to handle such complications. This along with concerns within the physician community of bleeding underlie US figures showing that t-PA is administered to less than 3% of acute ischemic stroke patients. Most patients therefore receive only palliative care. LeadDiscovery has recently updated a DiscoveryDossier describing studies by scientists at ThromboGenics Ltd demonstrating that deletion of the coagulation cascade protein, alpha-2-antiplasmin, reduces stroke in a model of total cerebral artery occlusion. This dossier also reports similar results on stroke reduction following the administration of pharmacologic doses of microplasmin, a truncated form of the natural protein (plasmin) bound by alpha-2-antiplasmin. Given these promising preclinical results, ThromboGenics are entering microplasmin into Phase I investigation in man thus advancing this strategy for the acute treatment of ischemic stroke. Free access to a full overview supporting this therapeutic use of microplasmin can be gained by clicking here. US researchers working in collaboration with ThromboGenics have recently published further data supporting this concept. This group embolized rabbits by injecting small blood clots into the cerebral circulation. Microplasmin, infusion starting 60min post-embolization, significantly reduced neurological deficits at 4 mg/kg. At this dose microplasmin was subsequently determined to be safe in a second model of stroke, since it did not increase the incidence of hemorrhages compared to vehicle-treated rabbits, nor did it significantly alter hemorrhage volume, infarct rate or volume. In contrast, t-PA, at a dose that reduced neurological deficits significantly increased hemorrhage rate compared to vehicle controls a finding that is in agreement with clinical data. This study therefore suggests that microplasmin may be as effective as t-PA in treating the effects of ischemic stroke, but with an improved safety profile. This supports the further development of microplasmin as an alternative to t-PA.. Microplasmin is now available as a licensing option. [for further details of this and other projects log on to TherapeuticAdvances]

Advances in the treatment of autoimmune disease

The American Autoimmune Related Disease Association lists over 50 different autoimmune diseases. Some of these are common such as rheumatoid arthritis which affects about 1% of all populations, women two to three times more often than men. This translates to a total of 5 million sufferers in the major pharmaceutical markets. The market for agents used to treat rheumatoid arthritis totaled $1.6 billion in 2000. According to some analysts, new therapeutic approaches will drive the market for autoimmune disorders such as rheumatoid arthritis to grow at a rate of over 15%, to a value of over $21 billion by 2006. At present, treatments of this disease are based on symptomatic therapies however the current trend is to move towards disease-modifying anti-rheumatic drugs (DMARDs). One particularly exciting drug discovery target is CD200, a molecule that is expressed on a subset of T cells, on all CD19-positive B cells, and is upregulated on most activated T cells. Researchers have found that that CD200 binds to a receptor thus regulating myeloid cell activity in a variety of tissues. Mice lacking CD200 have been found to suffer rapid onset of experimental autoimmune encephalomyelitis (a model of multiple sclerosis). Outside the brain, disruption of CD200-CD200 receptor interaction precipitated susceptibility to collagen-induced arthritis. Canadian researchers have now shown that the novel immunosuppressant molecule CD200Fc (linking an extracellular domain of CD200 with a murine IgG2a Fc region) can reverse established autoimmune arthritis in an animal model supporting the therapeutic potential of this molecule. This technology is currently being developed by the Canadian company Transplantation Technologies. [for further details of this and other projects log on to TherapeuticAdvances]

Therapeutic activity of new kinase modulator

Regular readers of TherapeuticAdvances will know about LeadDiscovery’s recent focus on kinases. In particular, our recent state of the art review of the therapeutic and pharmaceutical potential of glycogen synthase kinase assesses the potential of inhibitors of this enzyme as treatments of a variety of conditions including diabetes, Alzheimer’s disease, bipolar disorder and diseases associated with apoptosis (Click here for access). In our most recent edition of TherapeuticAdvances we highlight further evidence to support the development of GSK-3 inhibitors for the treatment of Alzheimer’s disease. We also describe the development of other kinase modulators, in particular Telik's TLK19780, a selective activator of the insulin receptor beta-subunit tyrosine kinase. This non-peptide small molecule has recently been shown to selectively enhance maximal insulin-stimulated insulin receptor autophosphorylation and insulin sensitivity. TLK19780 was shown to be rapid in action enhancing insulin-stimulated glucose transport and both the sensitivity and maximal responsiveness to insulin in adipocytes. These studies support the development of TLK-19781 as alternatives to nuclear hormone receptor agonists for the treatment of type 2 diabetes. An IND is expected to be filed for TLK-19781, another orally-active insulin receptor activator being developed by Telik, in 2003. Of interest to business development personnel, Telik and their collaborators, Sanwa are apparently jointly seeking a multinational partner for key markets other than Asia and Japan. [for further details of this and other projects log on to TherapeuticAdvances]

Please remember that you can learn more about the publications mentioned above by logging on to TherapeuticAdvances. This is completely free and without obligation, so why not click the link and pay us a visit. In addition please note that we are currently featuring 3 new reports:

  • Glycogen synthase kinase 3: Proof of concept and therapeutic opportunities for the treatment of diabetes, Alzheimer's disease, stroke & bipolar disorder [more]
  • Ion Channels as Therapeutic Targets for Multiple Diseases [more]
  • New Targets and Drug Discovery Platforms in Antifungal R&D [more]

Jon Goldhill

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

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