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Feature

Emerging Drug Discovery Targets

May 2nd, 2003 Posted on: 06 May 03

Summary

This edition of
TherapeuticAdvances: 27th February 2003

 

Emerging Drug Discovery Targets

from LeadDiscovery

2 May 2003

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"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/020503/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.

In this weeks edition:

  • MAPK/ERK-kinase inhibitors as a promising strategy for the treatment of neuropathic pain [more]
  • Targeting VEGF for the treatment of airway disease [more]
  • Aurora2 inhibitors for the treatment of cancer [more]
  • Advances from industry [more]
  • Today's breaking scientific publications for the drug development community [more]
  • This week's licensing opportunities including:
    • Targeting T-Cells to the Tumor Vasculature [more]
    • CXCR-4 blockers as a strategy for reducing metastasis[more]
  • New DiscoveryDossiers [more]:
    • Asthma Therapeutics: New treatment options and emerging drug discovery targets
    • The lymphoma market: Keeping up in a fragmented and competitive environment


MAPK/ERK-kinase inhibitors as a promising strategy for the treatment of neuropathic pain: Approximately 9% of the US population suffers from moderate to severe non-cancer-related pain, a figure that includes 40-70 million individuals with chronic pain. Consequently the development of analgesics has represented a major pharmaceutical objective. (click here for "Pain 2002", an analysis of future directions in analgesic therapeutics). One particular type of chronic pain, migraine is highlighted in the “Focus on Pain” section of our current edition of TherapeuticAdvances (Click here to access). Another type of chronic pain, neuropathic pain has many underlying causes and is notoriously difficult to treat using currently available therapeutics.

Approximately 26 million patients worldwide (10 million in the US) suffer from some form of neuropathic pain, spending an estimated $2-3 billion annually on treatments. This condition precipitates other serious conditions such as depression and is associated with an estimated pharmaceuticals market of US$18.7 billion worldwide. Due to the high incidence and the poor efficacy of current treatment for neuropathic pain, novel targets for this condition are being keenly sought. Of particular interest in this respect is a recent study conducted by researchers at Pfizer that identified changes in gene expression in streptozocin induced diabetic neuropathy. Expression of several key components of the extracellular signal-regulated kinase (ERK) cascade was found to be altered. In particular, levels of ERK1 and 2 correlated with the onset of streptozocin-induced hyperalgesia. Establishing the ERK cascade as a therapeutic target this group demonstrated that intrathecal administration of the selective MAPK/ERK-kinase (MEK) inhibitor PD 198306 dose-dependently blocked static allodynia in both the streptozocin and the chronic constriction injury models of neuropathic pain. Since intraplantar administration of PD 198306 had no effect in either model of hyperalgesia, changes in the activation of ERKs and the effect of MEK inhibition are localized to the central nervous system.

This study clearly demonstrates the proof of concept supporting the development of MEK inhibitors for the treatment of neuropathic pain. To date few selective MEK inhibitors have been developed and further development in this field may lead to the identification of molecules with considerable therapeutic and commercial value. Readers who are interested in developing novel MEK inhibitors should be aware of the “Kinase Enterprise Library” that LeadDiscovery has recently featured. This is a targeted library of candidate kinase inhibitors that is available for in house screening. Alternatively, options are available through which LeadDiscovery’s partner ChemOvation can dock this library into the active site of MEK using their suite of computational tools (Click here for further information on this library) [more on these findings]

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Targeting VEGF for the treatment of airway disease:  Asthma affects 155 million people worldwide. In the United States alone there has been a recent two-fold increase in the number of cases of asthma driving pharmaceutical market values up to as high as $8 billion worldwide. Despite a large number of drugs available to clinicians, up to 15% of patients suffer from uncontrollable disease symptoms, while many patients responding to their medication demonstrate poor compliance. Both of these factors increase the demand for novel therapies that possess new modes of action (see “Asthma Therapeutic: New treatment options and emerging drug discovery targets" - click here for access).

There is also a pressing need to develop new therapeutics for COPD, particularly those that control the underlying and largely untreatable inflammatory and destructive processes that cause its relentless progression (see "Therapeutic and pharmaceutical approaches to COPD" - click here for access). Worldwide, 600 million people suffer from COPD, with some three million dying from the disease each year representing a global market of US$2.8 billion.

As in all inflammatory diseases, there is increased oxidative stress in both allergic inflammation and COPD, as activated inflammatory cells produce reactive oxygen species. This suggests that antioxidants may be of use in the therapy of both COPD and asthma. However, existing antioxidants are weak and are not able to neutralize the high level of oxidative stress in the airways, and so more potent antioxidants are needed in the future. Alternatively therapeutic strategies could target the consequences of oxidative stress.

One such consequence is apoptosis and in an attempt to prevent this phenomenon mechanisms have evolved to stimulate compensatory angiogenesis. During anoxic conditions angiogenic factors including the prototypic VEGF are released. VEGF is able to stimulate the generation of new blood vessels and it is also able to prevent the death of existing endothelial cells. Asthma is associated with increased VEGF and angiogenesis. In contrast, field-leaders from the University of Colorado Health Sciences Center have reported that VEGF levels are reduced in the airways of patients with emphysema. This mirrors the death of endothelial and epithelial cells which together make up the alveolar septum a structure that separates adjacent alveoli and is responsible for gas exchange. On the other hand VEGF blockers promote alveolar cell apoptosis-dependent emphysema in rats. These studies underline the differences between asthma and COPD and support the concept that a failure of VEGF-related compensatory mechanisms may underlie the etiology of COPD. Very recently VEGF levels have been shown to correlate with disease severity such that mild emphysema is associated with an increase in protein levels while severe disease is characterized with decreased expression.

Most recently, Rubin Tuder from Johns Hopkins University School of Medicine, and colleagues have investigated further the role of reduced VEGF levels in lung alveolar septal cell apoptosis and emphysema. In particular the VEGF receptor blocker SU5416 was shown to increase alveolar enlargement, alveolar septal cell apoptosis, and expression of markers of oxidative stress. Each of these phenomena were prevented by the superoxide dismutase mimetic M40419. Furthermore, a broad-spectrum caspase inhibitor markedly reduced the expression of markers of oxidative stress induced by SU5416 treatment. These data suggest that VEGF limits oxidative stress and apoptosis, and that reduced levels of this growth factor during emphysema may therefore play an important role in tissue destruction associated with this disease. Hence strategies that prevent the reduction of VEGF or the endogenous administration of VEGF may represent novel treatments for patients with COPD. In the “Focus on Cardiovascular Disease” section of this edition of TherapeuticAdvances (Click here to access) we report a clinical trial demonstrating the safety and efficacy of endogenous administration of VEGF to patients with angina. A similar study in a cohort of COPD patients is eagerly awaited.[more on these findings]

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Aurora2 inhibitors for the treatment of cancer: Protein kinases are the second largest group of drug targets after G-protein-coupled receptors, and they account for 20-30% of the drug discovery programs of many companies. To date three protein kinase inhibitors have been approved for clinical use and a further 23 protein kinase inhibitors are known to be undergoing human clinical trials. This figure is set to increase since the protein kinases comprise the largest enzyme family with approximately 500 being encoded by the human genome. As described above, LeadDiscovery has recently featured the “Kinase Enterprise Library” which offers organizations the possibility of screening a targeted library of candidate kinase inhibitors against a wide variety of kinases (Click here for further information on this library). With tools like this becoming available it is now possible to rapidly identify novel lead inhibitors for kinases of interest. The challenge now is to establish the function of recently identified kinases, to establish a proof of concept for their inhibition, and to design inhibitors.

Kinases are particularly important in the etiology of cancer. Researchers at the University of Arizona have been focusing on the structure and function of oncogenic protein kinases such as Aurora 2 kinase and c-Kit. Aurora kinases are a family of mitotic serine-threonine kinases that are over-expressed in several solid tumors including pancreatic and colorectal cancer. They localize to the mitotic apparatus and regulate completion of centrosome separation, bipolar spindle assembly and chromosome segregation. Dysregulation of these kinases due to over-expression leads to defects in cytokinesis with subsequent polyploidy. The Arizona group have developed a structure-based novel small molecular inhibitor design program for several oncogenic protein kinases and have synthesized and tested these on a variety of cancer cell lines. Several small molecular inhibitors have been designed and synthesized based on existing ATP-binding site inhibitors. These are currently being evaluated in cancer cell lines, specifically pancreatic cancer cell lines.

Aurora1 or aurora2 inhibitors were designed first by demonstrating that there was significant homology between these kinases and bovine cAMP-dependent kinase (1CDK), murine cAMP-dependent kinase (1APM), and Caenorhabditis elegans twitchin kinase (1KOA) and then by building structural models of aurora1 and aurora2 using 1CDK as the template structure. Molecular dynamics and docking simulations targeting the ATP binding site of aurora2 were used to predict active-site residues that interact with reference kinase inhibitors and moieties that interact with these residues. Inhibitors with isoquinoline and quinazoline moieties were recognized by aurora2. The calculated binding energies for the docked small-molecule inhibitors were qualitatively consistent with the IC50 values generated using an in vitro kinase assay validating this in silico approach. The path is now open to dock libraries such as the Kinase Enterprise Library into the aurora2 template or to employ medicinal chemistry approaches to identify and optimize other aurora2 inhibitors [more on these findings]

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Advances from industry

  • PTB1B inhibitors from SUGEN: Obesity and comorbid type 2 diabetes represent a frequent and growing global problem. Protein tyrosine phosphatases (PTPs) represent a target for treatments of insulin resistance, a phenomenon associated with these conditions as well as a target for other serious condition. Many PTP inhibitors identified to date however are peptide-based and contain a highly charged phosphate-mimicking component. These compounds usually lack membrane permeability and this limits their utility in the inhibition of intracellular phosphatases. SUGEN have recently designed the first series of PTP inhibitors that do not suffer this problem [more]

New DiscoveryDossiers:

  • Asthma Therapeutics: New treatment options and emerging drug discovery targets [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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