11th July 2002
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LeadDiscovery regularly produces DiscoveryDossiers analyzing the proof of concept and drug development activity of various therapeutic targets. One such dossier that has generated a high level of recent interest and positive feedback focuses on COPD (Click here for access). World-wide, 600 million people suffer from COPD, with some three million dying from the disease each year due to the paucity of therapeutic advances in the treatment of this disease. Asthma affects fewer people and is responsible for fewer deaths, however its incidence is increasing and remains a serious condition. Considering these statistics it is not surprising that airway disease once again features heavily in TherapeuticAdvances, LeadDiscovery's review of cutting edge research with drug development potential.
The current immunological focus of airway disease research is over-shadowing, perhaps unfairly, the development of mucoactive agents. This class of drug is intended to increase the ability to expectorate sputum (for example by increasing mucus fluidity) or to decrease mucus hypersecretion. Although mucoactive agents are not designed to reduce inflammation they can do so indirectly by decreasing the incidence of infection. Furthermore, such therapeutics can improve the symptoms of COPD and asthma, both of which are characterized by mucus hypersecretion. The recent discovery that CaCC1, an ion channel which mediates mucus secretion, is upregulated in patients with bronchial asthma therefore has important implications for the targeted identification of novel mucoactive agents (as with all research projects described in this overview, this advance is discussed in greater detail on our website). A second biochemical change observed in both asthma and COPD is the over-production of TXA2.
This prostanoid TP receptor ligand is a potent constrictor of airway smooth muscle, an inducer of acetylcholine release and of airway microvascular leakage. It may also participate in the thickening and the remodeling of the asthmatic airway and in the thromboembolic events seen in about 28% of COPD patients. The ability to target TXA2 has recently been improved by Toronto based researchers. This group is targeting TXA2 through the development of a novel series of selective prostanoid TP receptor/thromboxane synthase blockers. Representatives of this series potently inhibit TP receptor mediated aggregation of human platelets, and are thus one of the most potent anti-aggregating substances so far described. Furthermore these therapeutic candidates also, at a similar concentration, inhibit thromboxane formation. An in vivo screening architecture was used to demonstrate that this series also opposed the vascular permeability and acute airway inflammatory and fibrotic effects. One group of targets that received particular attention in our recent dossier was the cathepsin family. Cathepsins K, S and L are macrophage-derived elastolytic cysteine proteases that are released from macrophages.
These cathepsins as well as cathepsin G have all been therapeutic targets for the treatment of COPD as well as a number of other inflammatory diseases. To date the development of cathepsin, especially cathepsin G, inhibitors have been largely unsuccessful. This situation appears to be changing as indicated by a recent report emerging from Johnson & Johnson, who have recently reported the development of a cathepsin G inhibitor with nanomolar potency. Finally, the IL-10 family also receives attention in this edition of TherapeuticAdvances, not only because of its potential importance in airway disease, but because it is implicated in many inflammatory conditions. Recombinant IL-10 has been shown to be of benefit in the treatment of IBD and psoriasis.
Recent studies have suggested that IL-10 is just one of a family of cytokines including IL-19, IL-20, IL-22, IL-24 and IL-26. Although the predicted structure of these molecules is conserved, certain receptor-binding residues are variable and define the interaction with specific heterodimers of different type-2 cytokine receptors. This leads, through the activation of signal transducer and activator of transcription (STAT) factors, to diverse biological effects. For example, IL-22 mediates acute-phase response signals in hepatocytes and IL-20 induces the hyperproliferation of keratinocytes, which has been proposed as a pathogenic mechanism of psoriasis. Thus the therapeutic potential of IL-10 and other members of this family is far from being fully exploited and further development should hopefully result in the identification in new and improved candidates for a variety of serious, debilitating and unmet diseases.
Although the STAT pathway originally emerged as the cytokine signal transduction mechanism, STAT1 has more recently been shown to mediate additional growth inhibitory signals. In the "Focus on Oncology" section of TherapeuticAdvances we report on data demonstrating that STAT1 expressed by tumor cells is a negative regulator of tumor angiogenesis both in its own right and also through its ability to enhance the therapeutic activity of IFN-related molecules. A further target to receive our attention because of its potential as an anti-cancer target is Laminin-1. This basement membrane protein promotes cell adhesion and migration, proteinase secretion and metastases of tumor cells and recent studies have identified ways in which it can be targeted to prevent metastatic progression. A further field that is receiving considerable attention due to its involvement in cancer is "Inhibitor-of-differentiation 2" (Id2). Inhibition of Id2 expression prevents neoplastic cell growth. More recently however, University of Tubingen researchers have shown that blocking Id2 also protects mice from neural apoptosis following cerebral ischemia. Continuing in the field of cardiovascular disease, we report in TherapeuticAdvances the development of a nitro-derivative of aspirin, NCX4016. Aspirin is given indefinitely following myocardial ischemia to prevent platelet aggregation and reduce the risk of both short- and long-term mortality and reinfarction rates.
Nitric oxide (NO) donors are also common adjuncts to thrombolytic therapy in patients with myocardial infarction. By developing a molecule that has the properties of aspirin but which also acts as an NO donor, NicOx have improved the therapeutic treatment of coronary artery disease. A further serious and unmet problem that sits at the crossroads of cardiovascular disease, inflammation and infectious disease is Sepsis. Occurring in 1-2% of hospital admissions, this condition is associated with 45% risk of mortality if it progresses towards septic shock making it the 11th most common cause of death in the US. In a recent DiscoveryDossier we describe exciting new strategies for blocking the effects of LPS, a gram-negative toxin. In this edition of TherapeuticAdvances, we focus on opportunities for targeting its gram-positive counterpart, LTA.
As our understanding of tumor progression has expanded, cardiovascular R&D has gradually started to overlap with that of oncology. This is due, in particular to advances in angiogenesis, however a related therapeutic domain has emerged that takes advantage of a number of molecules able to selectively destroy the tumor vasculature. One of the first examples of this was Group B streptococcus (CM101), a microbe known to cause respiratory distress in neonates as well as tumor reduction in adults. Vascular targeting agents are now receiving ever increasing attention and in this edition of TherapeuticAdvances, we report on studies showing that this class not only destroys the vasculature but also increase tumor sensitivity to standard chemotherapeutics. Angiogenesis research has now expanded to cover additional indications. In this edition of TherapeuticAdvances, we focus on one such indication, endometriosis. This is a common gynecological disorder defined by the proliferation of endometrial tissue outside the uterine cavity. The disease affects about 10% of all reproductive-aged women and the prevalence rises to 20%-50% in infertile women. The most widely accepted hypothesis is that endometrial cells are transported from the uterine cavity, then implant at ectopic sites. Retrograde flow of menstrual tissue through the fallopian tubes could cause intra-abdominal endometriosis. The clinical manifestations are pelvic pain, pelvic mass, alteration of menses, and infertility.
Some women with extensive endometriosis are asymptomatic, whereas some with minimal disease have incapacitating pain. In our "Focus on Angiogenesis" section we highlight a recent review that assesses different angiogenesis-related cytokines and growth factors that could represent future targets for the treatment of endometriosis. A second complaint that commonly affects women is rheumatoid arthritis. This is a chronic syndrome characterized by nonspecific, usually symmetric inflammation of the peripheral joints, potentially resulting in progressive destruction of articular and periarticular structures, with or without generalized manifestations. This disease is one of the more difficult of the autoimmune rheumatic diseases to control and can do the most damage to the joints. In this edition of TherapeuticAdvances, we identify a tetrapeptide derivative of human lactoferrin, PEP1261 as a lead for the treatment of this disease.
We finish of this review of our current edition of TherapeuticAdvances with potentially important news regarding obesity. We have recently published a full DiscoveryDossier giving an in depth analysis of what many consider to be one of the most promising target for obesity, ghrelin (Click here for dossier access). Another target that has also attracted considerable attention is the beta 3-adrenoreceptor. Up until recently the pharmaceutical industry has been unable to develop an agonist of this receptor that displays activity in obese humans, despite supportive data from the bench. Recently however Lilly researchers have published a paper describing how the novel beta3-adrenoceptor agonist, L-796568, increases lipolysis and energy expenditure by about 8% in overweight men. This is the first study to show such an effect of beta 3-adrenergic receptor agonists in humans without significant evidence for beta 2-adrenergic receptor involvement. Whether this effect is sustainable when administered chronically remains to be fully investigated. This publication rounds off what we believe to have been yet another fascinating fortnight in the world of drug discovery. Remember, further information regarding all the material featured in this overview can be found at our website.
Please note that we have also just published 2 new dossiers:
- Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer (Click here to access)
- Novel strategies for developing pro-apoptotic ceramidase inhibitors