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Emerging Drug Discovery Targets from Lead Discover

Posted on: 19 Mar 03

Summary

This week’s
TherapeuticAdvances: 27th February 2003

 

Emerging Drug Discovery Targets

from LeadDiscovery

19th March 2003

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In this weeks edition:

  • Target of the month - phosphoinositide 3-kinase (PI3K) [more]
  • Retinoids - from anticancer agents to anorectics and antiarthritics [more]
  • Adhesion molecules - emerging targets for airway disease [more]
  • Advances from industry [more]
  • Today's breaking scientific publications for the drug development community [more]
  • For this week's licensing opportunities please log on to TherapeuticAdvances [more]
  • New DiscoveryDossiers [more]:
    • 5-HT7 antagonists: Novel molecules for the unmet migraine prophylaxis market
    • Targeting endogenous inhibitors of apoptosis: Opportunities for the treatment of cancer, stroke and MS
    • Improved phytotherapeutic treatments for BPH (Licensing opportunity)
  • New services [more]:
    • Assay-ready kinase library

"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/120303/index.html


Target of the month - phosphoinositide 3-kinase (PI3K): The phosphoinositide 3-kinase (PI3K)/AKT1 pathway is acknowledged as a key component of cell survival. Activated by receptors or the small GTPase Ras, the various PI3K isoforms phosphorylate inositol lipids to form second messenger phosphoinositides. PI3K family members have long been accepted as oncogenes. An increase in copy number of specific PI3K genes or molecular mutation of these genes, leads to a "gain of function" reflected by a higher or a constitutive activation of PI3K activity and to the oncogenic transformation of many cell types.

PI3K is now viewed as a key player in many aspects of cell motility and adhesion and hence it is able to contribute to metastatic/invasive phenotypes of various cancer cells. Initial work on PI3K was however more focused on its function in cell growth and transformation and it is now clear that indirect or direct deregulation of PI3K causes aberrant cell-cycle progression and transformation of normal cells into tumor cells.

As well as playing a role in abnormal proliferation, PI3K is central to cell survival. Initial evidence was based on the ability of wortmannin to cause apoptosis in PC12 cells. The mechanism by which PI3K protects cells from programmed cell death has been the subject of intensive research and involves the downstream activation of the protein kinase Akt. PtdIns(3,4)P2 and PtdIns(3,4,5)P3 lipids produced by PI3K are able to bind Akt recruiting it to the plasma membrane where PDK1 and PDK2 phosphorylate it to its active form. This allows Akt to target proteins involved in cell death including members of the Bcl-2 family and caspase-9, protecting cells from apoptosis. In addition PI3K activation is able to increase the expression of members of the "Inhibitors of Apoptosis" family such as the c-IAPs (for a full analysis of this family Click here).

Disruption of the apoptotic pathways may account for resistance to chemotherapy and treatment failures in human neoplastic disease. Such treatment failure is well exemplified by acute promyelocytic leukemia. This cancer is responsive to both cytotoxic drugs that act through the stimulation of apoptosis as well as differentiating therapies, primarily retinoic acid (Click here to access our recent overview of retinoid therapeutics). Unfortunately however, remission is frequently only transient. The development of therapeutic approaches that overcome drug resistance is therefore of primary importance and in this respect considerable attention is being paid to the identification of p-glycoprotein inhibitors.

Due to the constitutive activation of PI3K in many cancers and the role of this enzyme in multiple aspects of cancer progression, inhibition of this enzyme has been investigated as a treatment for cancer. Moreover it is possible that PI3K inhibitors could serve to overcome drug resistance. To investigate this concept Italian researchers have recently investigated the effects of two inhibitors of PI3K, wortmannin and Ly294002, on the sensitivity of a drug resistant HL-60 clone to retinoic acid and pro-apoptotic molecules.

This clone was characterized by an increase in PI3K activity. Both wortmannin and Ly294002 were found to reduce phosphatidylinositol (3,4,5) trisphosphate levels and AKT1 activity and also to reverse resistance to several pro-apoptotic drugs (Camptothecin, Etoposide, Doxorubicin, Cytarabine, Mitoxantrone and Vincristine). Similarly, resistant cells overexpressing either dominant negative PI3K or dominant negative AKT1 became sensitive to these drugs. Conversely, if parental HL-60 cells were forced to over-express an activated AKT1, they became resistant to apoptotic drugs. This suggests that PI3K inhibitors can reintroduce sensitivity to apoptotic molecules.

Likewise, the inhibition of PI3K dramatically reintroduced sensitivity of the HL-60 cells to retinoic acid. Together therefore, these data strongly implicate PI3K and its down-stream signaling pathway in drug resistance in myeloid leukemia and suggests that PI3K inhibitors may be of particular therapeutic benefit. Due to the wide-ranging involvement of PI3K in many different aspects of tumor progression, the therapeutic benefit of such molecules is expected to extend to multiple types of cancer. Despite this potential however, little activity has been reported regarding the development of candidate PI3K inhibitors.

In order to help speed the development of kinase inhibitors, ChemOvation, a leading provider of medicinal chemistry services to both pharmaceuticals and biotechnology sectors has designed a "Kinase Enterprise Library". This library was designed using proprietary informatics tools, and represents a diverse collection of compounds based on 15 different templates. The potential importance of this library is increased by also including modelling filters such as AMDE and physio-chemical parameters. The templates are unique to ChemOvation and are available on a non-exclusive basis through LeadDiscovery's PharmaceuticalSolutions service. This library can be supplied for in house screening for PKI3 inhibitors or alternatively screening can be performed by Chemovation. In either case follow of services are offered to optimize hits [adapted from TherapeuticAdvances 12th March, 2003 click here]

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Retinoids - from anticancer agents to anorectics and antiarthritics:  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 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. As our understanding of the retinoids increases so too will their benefit in the field of oncology. More recently the retinoids have been developed as anorectics and only last month, BMS researchers published the first evidence linking this class to arthritis.

Anticancer indications

The potential of the retinoids to prevent breast cancer was noted almost 20 years ago. One retinoid that has attracted particular attention with respect to breast cancer is 4-HPR (retinamide; fenretinide). Initial preclinical studies indicated that 4-HPR can suppress carcinogen-induced mammary cancer in rats; subsequent phase III trials demonstrated that 4-HPR can prevent second breast malignancies in premenopausal women with early breast cancer. In contrast 4-HPR is ineffective in patients with advanced disease. Breast cancer, like many other cancers is characterized by the absence and abnormal regulation of RAR beta receptors and expression of the RAR beta gene restores retinoic acid sensitivity to breast cancer cells. Understanding the mechanisms responsible for loss of receptor activity should facilitate the therapeutic use of the retinoids. Our recent dossier repeatedly underlines the importance that histone acetylation/methylation plays in the biology of the retinoid.

The concept that chromatin structure is plastic and that this represents a key mechanism in the regulation of transcriptional control is now generally accepted. This plasticity is regulated by histone (de)acetylation (Click here to access "Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer") and methylation. Correspondingly, defects in acetylation and/or methylation have been proposed to play a central role in cancer, while on the other hand therapeutics that modulate histone deacetylase or methylase activity hold considerable potential for the treatment of cancer. CpG island hypermethylation is known to be associated with gene silencing in cancer, and these silenced genes can be reactivated by 5-aza-2'-deoxycytidine (5-Aza-CdR), a potent inhibitor of DNA methylation. Japanese researchers have recently reported that 5-Aza-CdR treatment resulted in complete demethylation of the RAR beta 2 gene in a breast cancer cell line and that this was accompanied by cell cycle arrest and time-dependent growth inhibition. This finding therefore brings together the two cutting edge fields of histone plasticity and retinoid biology and perhaps more importantly demonstrates how the tumor suppressive effects of the retinoids can be reintroduced into cancer cells through the inhibition of DNA methylation [for further details of this research click here]

Improving options for the treatment of metabolic disorders

Obesity represents a global problem with high associated mortality and co-morbidities, and the world obesity market has been predicted to reach $3.7 billion by 2008. The drive to develop new treatments for obesity is therefore immense. Ghrelin represents one particularly promising breaking targets in the field of obesity prompting LeadDiscovery to produce a DiscoveryDossier analyzing this field (Click here for access).

Many of the problems related to obesity are due to the development of insulin resistance and diabetes and the development of agents able to both reverse insulin resistance and reduce body weight may be particularly beneficial. The peroxisome proliferator-activated nuclear receptor (PPAR) family has received particular scrutiny and as a result the thiazolidinediones have emerged as a therapeutic class for the treatment of diabetes. First generation thiazolidinediones were agonists of the PPARgamma receptor and were able to reduce insulin resistance. One adverse effect associated with PPARgamma receptor agonists is however weight gain. Given the comorbidity of type II diabetes and obesity this can limit the usefulness of such molecules. Quite unexpectedly, a moderate reduction of PPARgamma activity observed in heterozygous PPARgamma-deficient mice, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. Consequently PPARgamma antagonists are now being developed.

More recently molecules have been developed that activate PPARalpha. This class is able to reduce triglyceride levels and is also able to improve insulin sensitivity and as a result dual PPARalpha/PPARgamma agonists have been developed with proposed beneficial effects over existing PPARgamma- and alpha-preferential drugs, respectively, in treatment of type 2 diabetes.

PPAR receptors exist as heterodimers along with the retinoid X receptor (RXR) and like the PPARs, the retinoids have also been attracting considerable attention due to their potential to regulate metabolic imbalance as well as the proliferation of cancer cells. Of particular interest Ligand Pharmaceuticals have recently developed a RXR:PPARgamma ligand.

Given the potential role of RXR ligands in the treatment of metabolic disease UCLA researchers have recently investigated the effects of RXRalpha gene deletion on various metabolic parameters. Hepatocyte RXRalpha-deficient mice fed a high-saturated-fat diet were found to have increased leptin levels. This was related to reduced food intake and improved glucose tolerance suggesting that RXRalpha antagonists may confer therapeutic advantage in obese diabetes. Improved glucose tolerance was related to increased IGF-I levels. Unfortunately, body weight and fat content were significantly higher in these mutant mice due to defective control of fatty acid metabolism and a compromised PPARalpha-mediated pathway.

This body of data confirms the ability of RXR antagonists to exert some beneficial effects in metabolic disorders increasing energy consumption, reducing food intake and improving glucose tolerance. On the other hand deleting the RXR receptor promotes obesity. Since RXR forms heterodimers with both PPARalpha and PPARgamma blocking RXR may produce a phenotype that shares some similarities with PPARalpha deletion and others with PPARgamma deletion. Since therapeutic candidates that target PPAR may confer most benefit in the context of diabetes and obesity if they activate PPARalpha and/or block PPARgamma it is conceivable that RXRalpha antagonists may be of use if they are selective for RXR:PPARgamma heterodimers and fail to impede RXR:PPARalpha mediated effects. This is supported in part by recent research showing that the dual antagonism of RXR and PPARgamma decreases triglyceride content, potentiates leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating diet-induced obesity and insulin resistance. Molecules that block RXR:PPARgamma and stimulate RXR:PPARalpha dimers may represent an even better approach [for further details of this research click here]

Arthritis as an emerging target for the retinoids?

Rheumatoid arthritis affects about 1% of all populations, women two to three times more often than men. This translates to a total of 5 million rheumatoid arthritis sufferers in the major pharmaceutical markets. The market for agents used to treat rheumatoid arthritis totaled $1.6 billion in 2000. At present, treatments of this disease are based on symptomatic therapies such as NSAIDs (including the new COX-2 inhibitors), gold-containing compounds and corticosteroids. The current trend however is to move towards disease-modifying anti-rheumatic drugs (DMARDs). The matrix metalloproteinases (MMPs) are implicated in joint destruction and inhibitors of for example MMP-1 may provide therapeutic benefit. As an alternative to the use of inhibitors, blocking MMP-1 expression may also be of use.

While the retinoids have more traditionally been used to treat cancer and various skin conditions recent data suggests a role in arthritis therapeutics. Specifically, a novel retinoic acid receptor (RAR) antagonist (BMS-189453) reduced MMP-1 expression in synovial fibroblasts. Furthermore, BMS-189453 treatment blocked the clinical progression of arthritis beyond soft tissue inflammation in collagen induced arthritis. In a second model of arthritis BMS-189453 treatment significantly reduced swelling with no notable progression to joint distortion/destruction. As well as reducing MMP-1 expression BMS-189453 also prevented the overexpression of MMP-13 and MMP-3 in arthritic joints. This is the first study to show the clinical potential of RAR antagonists in arthritis [for further details of this research click here]

[to request a full evaluation of any of these areas & related medicinal chemistry opportunities visit CustomReports]

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Adhesion molecules - emerging targets for airway disease: Over 750 million people world-wide suffer from chronic respiratory tract diseases such as asthma and COPD (chronic obstructive bronchitis and emphysema) and together these conditions drive an annual market in excess of $10 billion worldwide. There is considerable demand for new therapeutic options that target the inflammatory components of both of these conditions. In this respect targeting the adhesion molecules may be of particular use.

As described in our recent analysis of therapeutic targets for the treatment of COPD (Click here for access), preventing the recruitment of neutrophils, monocytes and cytotoxic T cells into the lungs and respiratory tract may be of benefit to patients with emphysema or chronic bronchitis. For example, preventing the interaction of E-selectin on endothelial cells interacts with sialyl-Lewis x on neutrophils may limit the severity of COPD. Likewise, the expression of Mac-1 (CD11b/CD18) is increased on neutrophils of patients with COPD, suggesting that targeting this adhesion molecule, which is also expressed on monocytes and macrophages, might also be beneficial.

In a soon to be published dossier reviewing emerging therapeutic targets for asthma we highlight VCAM1. The interaction between VLA-4 and VCAM-1 is important for eosinophil inflammation, a hallmark of asthma. Humanized antibodies to VLA-4 have been developed as have small molecule peptide inhibitors of VLA-4 which are effective in inhibiting allergen-induced responses in sensitized sheep. Small molecule non-peptide inhibitors of VLA-4 are also now in development for asthma. Merck researchers have recently reported one such molecule which, when administered intranasally, dose-dependently inhibited eosinophilia and eosinophil activation in an ovalbumin model of allergic airway disease [for further details of this research click here]

[to request a full evaluation of this area & its medicinal chemistry opportunities visit CustomReports]

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Advances from industry (12th-19th March)

  • Miglustat: Actelion has launched Oxford GlycoSciences' glucosyl transferase inhibitor, miglustat (ZAVESCA) in the UK, its first market worldwide. The agent is indicated for the treatment of mild to moderate type I Gaucher's disease in patients for whom enzyme replacement therapy is unsuitable. Further launches are expected in the EU during 2003. Actelion obtained worldwide marketing rights, excluding Israel, for miglustat from Oxford GlycoSciences as part of a licensing agreement extension in November 2002.
  • Vardenafil: Bayer and GlaxoSmithKline announced that the European Commission has granted vardenafil (LEVITRA), a phosphodiesterase V inhibitor, marketing authorization for the treatment of erectile dysfunction. The decision follows a positive opinion by the European CPMP on 21 November 2002. Vardenafil has been approved in Mexico and Paraguay and approval is pending in the USA, Canada, South Africa and Japan.

New DiscoveryDossiers:

  • 5-HT7 antagonists: Novel molecules for the unmet migraine prophylaxis market [More]
  • Targeting endogenous inhibitors of apoptosis: Therapeutic Opportunities [More]
  • Improved phytotherapeutic treatments for BPH [More]


New service:

In 2003, following the launch of a major collaboration between LeadDiscovery and ChemOvation PharmaceuticalSolutions was expanded to integrate the target identification and preclinical development services of LeadDiscovery with the medicinal chemistry expertise of ChemOvation. As a result PharmaceuticalSolutions can now offer a seamless path from DiscoveryDossiers all the way through to lead identification. As part of this service the drug development sector is offered a number of highly targeted libraries [more]


Dr Jon Goldhill

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

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