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Emerging Drug Discovery Targets

29 May 2003 Posted on: 30 May 03

Summary

This edition of
 

Emerging Drug Discovery Targets

from LeadDiscovery

29 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. 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:

  • Retinoids as inhibitors of I-kappaB kinase (IKK) and blockers of tumor progression [more]
  • Targeting Natural Killer T cells for the treatment of asthma [more]
  • Emerging indications for vitamin K mimics - opportunities for osteoporosis, atherosclerosis and cancer therapeutics [more]
  • Successful Kv1.5 gene therapy of pulmonary hypertension (plus information on the assay ready "potassium channel enterprise library") [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/Chemistry Libraries [more]:
    • Asthma Therapeutics: New treatment options and emerging drug discovery targets
    • Cancer Immunotherapy R&D
    • Potassium Channel Enterprise library


Retinoids as inhibitors of I-kappaB kinase (IKK) - oncology candidates: The retinoids play a key role in differentiation, proliferation and apoptosis. Since each of these processes play a part in tumor progression almost 20 naturally occurring and synthetic analogs of retinoic acid are now either in development or on the market as anti-cancer treatments. Although efficacy has been demonstrated in acute promyelocytic leukemia and various skin cancers, the extension of therapeutic benefit to other cancers 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 and strategies for improving their therapeutic efficacy.

Most retinoids developed to date target the nuclear retinoid receptors however certain synthetic retinoids are able to stimulate apoptosis without binding to retinoid receptors. This may lead to the development of molecules with multiple mechanisms of action and with possible improvements in efficacy. Studies by Javi Piedrafita and colleagues at Sidney Kimmel Cancer Center, San Diego, have revealed that these retinoids prevent the activation of NF-kappaB.

NF-kappaB is overexpressed or constitutively activated in many cancer cells, where it induces the expression of antiapoptotic genes correlating with resistance to anticancer therapies. In particular NF-kappaB induces the expression of IAP-1, IAP-2 and XIAP, three endogenous inhibitors of apoptosis that represent highly promising targets for oncology therapeutics (click here for our recent DiscoveryDossier on this subject). Small molecules that inhibit the NF-kappaB signaling pathway could therefore be used to induce apoptosis in NF-kappaB-overexpressing tumors and potentially serve as anticancer agents. This concept is further supported by data showing that NF-kappaB also plays a key role in angiogenesis and cellular proliferation.

Activation of NF-kappaB normally requires the phosphorylation and subsequent degradation of I-kappaB by I-kappaB kinase (IKK). Inhibitors of IKK therefore represent a therapeutic target for blocking the NF-kappaB signaling pathway and hence tumor progression. Molecules with a similar structure to the retinoid antagonist MX781 may be of particular interest since Javi Piedrafita’s group has recently shown that this compound is able specifically and reversibly inhibit both IKKalpha and IKKbeta. This was paralleled by a complete inhibition of tumor necrosis factor alpha-mediated binding of NF-kappaB to DNA and correlated with reduced cell proliferation, reduced expression of IAP-2 and increased apoptosis. This pro-apoptotic activity was dependent on caspase activity but independent of the retinoid receptors.

These data have a number of important implications. Firstly, they offer proof of concept to support the development of IKK inhibitors as treatments of cancer. Secondly, molecular design based on the structure of MX781 may lead to the development of IKK inhibitors whose therapeutic activity is enhanced by additional retinoid receptor mediated activity. Finally, the kinase enterprise library recently featured by LeadDiscovery (Click here for further information on this library) could be screened in silico for molecules based on the structure of these retinoids in order to fast track the development of IKK inhibitors [more on these findings]

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Targeting Natural Killer T cells for the treatment of asthma:  As described in our recent DiscoveryDossier “Asthma Therapeutics: New treatment options and emerging drug discovery targets” co-produced with Professor Peter Barnes (click here for access), the incidence of asthma has dramatically increased over recent years. This represents a profound public health problem, each year responsible for 9 million visits to health care providers, over 1.8 million emergency room visits, and over 460,000 hospitalizations in the US alone. As well as placing a considerable burden in terms of direct medical costs, asthma is one of the leading causes of work or school absenteeism. Paralleling the dramatic growth in its incidence, asthma is driving one of the most rapidly growing global therapeutic markets. The impact that increased incidence is having on therapeutic market values is further increased by a considerable degree of under-treatment of asthma. Global revenue for 2001 from asthma therapies has been reported by some to be as high as $11.7 billion and up until recently annual growth rates of 10-15% have been reported. Most sources however predict that this level of growth is not sustainable. The anti-asthmatic market is well served by existing therapies, such as the beta2-agonists and corticosteroids that can treat 95% of asthma patients. Competition within the anti-asthmatic market will therefore grow increasingly intense. Future asthma therapies will focus on the treatment of patients whose condition is not satisfactorily controlled by currently used approaches and on the improvement of patient compliance that is currently very poor, especially with respect to inhaled treatment.
NK cells, components of the innate immune system, have been associated with immune surveillance of tumor cells and defense mechanisms against various pathogens. The earliest contact between antigen and the innate immune system is thought to direct the subsequent antigen-specific T cell response. Since NK cells are normally present in considerable numbers in human lung interstitium, these cells may also play a role in the response of the asthmatic airway to allergen. Indeed patients with asthma show increased numbers of NK cells and stronger NK activity in peripheral blood than normal healthy blood donors.

In 1999 Korsgren et al reported that depletion of NK1.1+ cells inhibits pulmonary eosinophil and CD3+ T cell infiltration as well as increased levels of IgE, IL-4, IL-5, and IL-12 in bronchoalveolar lavage fluid in a murine model of allergic asthma. More recently, researchers at Stanford University reported that allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma, does not develop in the absence of a specific type of T cell with NK function, V(alpha)14i NKT cells. The failure of NKT cell-deficient mice to develop AHR is not due to a general inability of these mice to produce Th2 responses because NKT cell-deficient mice that are immunized subcutaneously at non-mucosal sites produce normal Th2-biased responses. The failure to develop AHR appears to be related to changes in pathways governing the antigen-stimulated levels of IL-4 and IL-13, two cytokines, which as described in our recent dossier are key to the asthma process, and which, at least with respect to IL-13, represent very promising targets for asthma therapeutics. Thus, pulmonary V(alpha)14i NKT cells crucially regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens. Therapies that target V(alpha)14i NKT cells may therefore be clinically effective in limiting the development of AHR and asthma [more on these findings]

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Emerging indications for vitamin K mimics - opportunities for osteoporosis, atherosclerosis and cancer therapeutics: Vitamin K was discovered in 1929 as an essential factor required for normal hemostasis, but it was not until 1974 that it was found out that vitamin K functions as a cofactor for the enzyme gammaglutamyl carboxylase in the synthesis of an unusual amino acid called gammacarboxy glutamate (Gla). Vitamin K is a group name for a number of related compounds which share a naphthoquinone nucleus including vitamin K1, K2 and K3. Gla is important for the biological functioning of a number of proteins involved in bone structure and hence, as described in a recent DiscoveryDossier (click here for access), vitamin K represents an excellent target for the development of new treatments of osteoporosis. In contrast to vitamin K1 and independent of gammaglutamyl carboxylase activity, vitamin K2 has been suggested to modulate the prenylation of growth factors required for osteoclast activation thereby inhibiting osteoclastogenesis. Hence vitamin K2 mimics may be of particular use in the treatment of osteoporosis.

In addition to representing a treatment for osteoporosis, K vitamins, also inhibit cell growth both in vitro and in vivo, with vitamin K3 being more potent than vitamin K1 and K2. In 1995, University of Pittsburgh researchers synthesized a thioalkyl analog of vitamin K (2-(2-mercaptoethanol)-3-methyl-1, 4-naphthoquinone; Cpd 5) which was able to interact with cellular thiols or thiol-dependent proteins. This interaction was via position 3 of its quinoid nuclei.

In particular, Cpd 5 has been suggested to arylate catalytic cysteine(s) found in protein tyrosine phosphatases (PTPases) thereby inactivating them. The Cdc25 phosphatase family is one family of PTPases that has an essential role in cell cycle progression, representatives of which activate Cdks. Treatment of cells with Cpd 5 has been shown to block Cdc25C. This prevents the activation of the mitotic kinase Cdc2/cyclin B, which is required for entry into mitosis. Likewise Cpd 5 also inhibits Cdc25A which is responsible for the activation of Cdk 4, an important regulator for G(1) progression. In addition to activating the Cdks directly, Cdc25 is also able to activate ERK kinase and the ability of Cpd 5 to cause a sustained increase in the phosphorylation of ERK/MAP kinase further reduces the activity of Cdks. This confers potent growth inhibitory activity to Cpd 5 and its analogues in at least 13 different human cancer cell lines.

Most recently the University of Pittsburgh Group in collaboration with researchers at the Academia Sinica in Taiwan and at the CNRS in France published a thorough evaluation of the effects of Cpd 5 on cell cycle proteins. This study demonstrated that Cpd 5 decreased the levels of cyclin D1, Cdk4, p16, p21 and cyclin B1. The main effects of Cpd 5 were on G1 and S phase proteins, especially Cdk4 and Cdc25A contrasting with Vitamin K3. Computer docking studies of Cpd 5 and Vitamin K3 to Cdc25A phosphatase showed three binding sites. In the best conformation, Cpd 5 was found to be closer to the enzyme active site than Vitamin K3. These findings confirm that Cpd 5 represents a new class of anticancer agent, being a protein tyrosine phosphatase antagonist that binds to Cdc25A with suppression of its activity. Tumors expressing high levels of oncogenic Cdc25A phosphatase may thus be susceptible to the growth inhibitory activities of this class of compound and the further development of this therapeutic candidate and related compounds is eagerly awaited [more on these findings]

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Successful gene therapy of pulmonary hypertension: Pulmonary hypertension (PHT) exists in a rare primary form (which occurs in familial and sporadic forms) called pulmonary arterial hypertension (PAH) and a relatively common form of secondary PHT, as occurs in patients with heart disease, chronic lung disease (COPD), sleep apnea etc. Due to the high incidence of these conditions the number of patients with secondary PHT is large however many of these are undiagnosed and the actual frequency of secondary PHT is therefore unknown. As an indicator however, in individuals older than 50 years of age, cor pulmonale, the consequence of untreated PHT, is the third most common cardiac disorder. Cardiac diseases produce secondary PHT via volume or pressure overload; although vascular remodeling of pulmonary resistance vessels adds an obstructive element. The pulmonary circulation manifests, in varying degrees, excessive vasoconstriction, obstructive vascular remodeling, inflammation and thrombosis in situ. These changes narrow or obliterate the pulmonary artery lumen, which increases right ventricular afterload and ultimately precipitates failure of the afterload-intolerant right heart. Vascular remodelling changes along with pulmonary vasoconstriction are the mechanism of PHT in respiratory diseases. Unrelieved PHT, regardless of the underlying cause, leads to right ventricular failure and can cause death.

Although the pathophysiology of PHT is unclear, K+ channels appear to be involved in this disease. Hypoxia has been shown to selectively inhibit the function and expression of voltage-gated K+ channels (Kv) in pulmonary arterial smooth muscle cells. Acute hypoxia inhibits Kv channel function, inducing membrane depolarization and a rise in cytosolic Ca2+ that triggers vasoconstriction. Chronic hypoxia may inhibit Kv channel activity by directly or indirectly downregulating mRNA and protein expression of Kv channel subunits. In particular the expression of O2- and 4-aminopyridine (4-AP)-sensitive, voltage-gated K channels (Kv1.5 and Kv2.1) is reduced. Hence gene therapy strategies that reintroduce Kv channel activity may be of therapeutic use. Field leaders from the Vascular Biology Group at the University of Alberta in Canada have recently investigated this possibility.

In their recent publication, Drs. Stephen Archer, Evangelos Michelakis and colleagues report the effects of Kv1.5 gene therapy in a chronic hypoxia model of rat PHT. Nebulization of rats with the human Kv1.5 gene (delivered in an adenoviral vector with a GFP reporter) produced an airway selective overexpression of the Kv1.5 channel and reversed changes in cardiac indices of rats subjected to chronic hypoxia back towards normoxic levels; in particular, changes in pulmonary vascular resistance. This study not only demonstrates the feasibility of airway delivery of the Kv1.5 gene but it also establishes a therapeutic proof of concept for this approach. Further advances in this technology that may allow prolonged overexpression of Kv1.5 through gene therapy are eagerly awaited. Alternatively the development of Kv1.5 channel openers may offer an alternative approach to the treatment of PHT and readers may be interested to learn about the "Potassium channel Enterprise library" an assay ready library of candidate potassium channel modulators which may be used to screen for therapeutic candidates targeting multiple potassium channels and indications (for further details of this library click here). [more on these findings]

Does your company require an expert analysis of PHT drug discovery targets /pharmaceutical potential? If so please read about our custom report service

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Industry news

  • Carvedilol: The US FDA has approved GlaxoSmithKline’s carvedilol (COREG), a nonselective beta blocker, for use in patients who have had a myocardial infarction and who have left ventricular dysfunction. The approval was based on results from the CAPRICORN (CArvedilol Post infaRction survIval COntRol in left ventricular dysfunctioN) trial, which showed that when carvedilol therapy was initiated within 21 days following a myocardial infarction in patients with left ventricular dysfunction, the risk of dying was reduced by 23%, when carvedilol was maintained long-term. Carvedilol is marketed worldwide for the treatment of hypertension, angina and heart failure.
  • Vilazodone: Merck KGaA and GlaxoSmithKline announced that results from a recently completed phase IIb trial of vilazodone showed that progression to phase III studies is not warranted. As a result, GlaxoSmithKline will return all rights to the agent to Merck KGaA. The latter will evaluate further options with respect to the development of the compound. Vilazodone, a selective serotonin reuptake inhibitor and 5HT1A partial agonist, was discovered by Merck KGaA as a potential therapy for depression.
  • Anidulafungin: Vicuron has submitted an NDA to the US FDA, seeking approval of its antifungal echinocandin, anidulafungin, for the treatment of esophageal candidiasis. The NDA submission was largely based on results from a pivotal phase III trial, demonstrating that intravenous anidulafungin was as effective as oral fluconazole in treating esophageal candidiasis. Additionally, anidulafungin was well tolerated with an adverse event profile comparable to oral fluconazole.
  • Gefitinib: AstraZeneca’s gefitinib (IRESSA), an epidermal growth factor receptor tyrosine kinase inhibitor, has been approved by the US FDA for the treatment of advanced nonsmall cell lung cancer (NSCLC). In addition, the Australian Therapeutic Goods Administration has approved the agent for the treatment of patients with locally advanced or metastatic NSCLC who have previously received chemotherapy. The agent is marketed in Japan and approval is pending in Europe.
  • Bortezomib: Millennium’s small molecule proteasome inhibitor, bortezomib (VELCADE), has been launched in the USA, following approval from the FDA, for the treatment of multiple myeloma in patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. Approval for this indication is pending in Europe, where an MAA was submitted in February 2003. Bortezomib is also under development for the treatment of other cancers including metastatic colorectal cancer, nonsmall cell lung cancer and chronic lymphocytic leukemia

Daily alerts announcing breaking scientific publications and press releases of importance to the drug discovery community are delivered through LeadDiscovery's free service, DailyUpdates. To register for this service please go to http://www.leaddiscovery.co.uk/dailyupdates%20registration.html


New DiscoveryDossiers:

  • Asthma Therapeutics: New treatment options and emerging drug discovery targets [More]
  • Cancer Immunotherapy R&D [More]
  • Potassium Channel Enterprise library [More]

LeadDiscovery

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

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