29th May 2002
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Another two weeks have passed, and once again our TherapeuticAdvances selection team has identified a series of publications considered to have excellent drug discovery potential. Although TherapeuticAdvances spans 16 different focus sections our current bulletin has a distinct inflammatory flavor.
Anyone who can remember back to the early days of signal transduction research will recollect how phospholipase A2 (PLA2) emerged as a key mediator of cell signaling. More recently however, a family of secreted PLA2 enzymes has been characterized. It is now known that this family is comprised of at least 10 members with distinct cellular distribution and growing therapeutic potential. Perhaps the most well known member of the sPLA2 family is sPLA2-IIA. Feebly expressed under normal circumstances, this enzyme becomes highly expressed during inflammation and sepsis. sPLA2-IIA has become associated with allergic rhinitis, rheumatoid arthritis, septic shock and ARDS. Other members of the sPLA2 family, in particular sPLA2-V and sPLA2-X, have interesting distribution patterns. Both enzymes are selectively expressed in human airway epithelium and in the case of sPLA2-X, in various immune cells. The secreted PLA2 enzymes thus have considerable untapped potential particularly in the field of inflammatory disease and thus form the focus of our "Target of the month" section.
TherapeuticAdvances' "Focus on Airway Disease" continues the inflammatory theme highlighting a series of new small molecule inhibitors of alpha4beta1/VCAM-1 interaction developed by Pfizer. This series prevented airway eosinophilia in models of airway inflammation supporting their development as treatments of diseases such as asthma. This common and growing condition is also the subject of "Focus on Industrial Development". Chemokine receptors have represented an area of growth over the past few years. This is especially relevent to Th2 cells that preferentially express a number of chemokine receptors including CCR4, CCR8, and CxCR4. At least 7 CxCR4 receptor antagonists have been developed, however this has generally been for the treatment of HIV-1 infection and/or cancer. Researchers at the University of Michigan have thus advanced the field by demonstrating that AnorMED's AMD-3100 can reduce a number of pathological parameters related to asthmatic-type inflammation.
This helps AnorMED who have been looking for a new indication for this series of drugs ever since AMD-3100 failed to meet the criteria for anti-HIV-1 efficacy in its Phase Ib/IIa trials. Furthermore this data convincingly shows the role that CxCR4 receptor antagonists may play a role in treating airway inflammation. The final publication to focus on inflammation centers on Cyclosporin A. This immunesuppressant is used in a number of inflammatory conditions such as IBD, rheumatoid arthritis, psoriasis and under certain conditions, asthma. Side effects have precluded the full use of this drug. Our "Focus on Immunology and Inflammatory Disease" highlights a new Cyclosporin A-like molecule, D-43787. Like Cyclosporin A, this novel molecule binds to cyclophilin, suppresses Th2 activity and exhibits therapeutic activity in models of asthma and arthritis. Unlike Cyclosporin A however, D-43787 fails to affect the activity of calcineurin. The hope therefore is that D-43787 may share the therapeutic activity, but not the side effects of Cyclosporin A.
Like Cyclosporin A, the NSAIDs represent classic treatments of inflammation. There is growing evidence, however that NSAIDs may offer uses far exceeding their original therapeutic indications. In particular, NSAIDs may have anti-cancer activity and indeed, following their successful launch as improved analgesics, COX-2 inhibitors are now being developed with this activity in mind. Metabolites of Sulindac, which is a non-selective COX inhibitor, are also able to inhibit cell proliferation and in "Focus on Oncology" we report a publication describing the development of novel Sulindac analogues that block the tumorigenic Ras/Raf/MAPK pathway. Another strategy being developed for the treatment of cancer is the stimulation of apoptotic mechanisms. These mechanisms are defective during tumor progression, due in part to "Inhibitors of apoptosis" (IAP). Survivin presents the strongest evidence for IAP involvement in cancer. Although not observed in adult differentiated tissue, this IAP is present in most transformed cell lines and cancers tested to date.
Even more importantly, survivin expression appears to be homogenous within the tumor environment, a feature unusual in a disease characterized by spontaneous mutation. Survivin has been shown to inhibit caspase directly and apoptosis in general, moreover survivin protein levels correlate inversely with 5-year survival rates in colorectal cancer. Thus there is considerable hope that targeting survivin could sensitize tissue to treatments that induce apoptosis. "Focus on Targeted Cancer Therapy" raises the possibility that survivin may also represent a target for vaccines and targeted immunotherapies. This is particularly intriguing given the possibility that a combination of neutralization and targeted immunotherapy could offer synergistic activity since the former would sensitize cells to the pro-apoptotic activity of the latter. Depleting polyamine pools represents one way of stimulating apoptosis.
"Focus on Metastasis" highlights the work of Italian researchers who have shown that this strategy can also prevent metastasis. Remarkably this phenomenon was independent of effects on local invasion. IAPs such as survivin can render cancerous cells resistant to therapeutic treatment " a similar effect can be evokes through the expression of p-glycoprotein. This transporter prevents the intracellular accumulation of small molecules, however it also plays a role in the movement of molecules across the blood brain barrier and in the apoptosis of immune cells. P-glycoprotein inhibitors or substrates are thus likely to play a major role in the treatment of various disease states. "Focus on Cell Death" acknowledges this, highlighting the efforts of Eli Lilly scientists who have developed pharmacophores of p-glycoprotein. These molecular models were then used to predict with accuracy molecules able to interact with p-glycoprotein. Finally, although chemotherapies have usually been used to kill cancer cells directly, Japanese scientists have recently developed a strategy enabling such treatments to be targeted towards the tumor vasculature. "Focus on Angiogenesis" highlights this work, describing the development of pentapeptides able to target liposomes carrying chemotherapies to blood vessels supplying tumors. This approach appears to work as dramatic tumor shrinkage was observed.
A number of thrombolytic approaches have been developed based on endogenous thrombolytics. The best known are t-PA and urokinase and synthetic forms of both have been developed. Urokinase was however withdrawn from the market and prourokinase has attempted to fill the resultant vacuum. Prourokinase is an inactive precursor of urokinase that is currently undergoing clinical trials by Abbott for a variety of indications including cerebral ischemia and peripheral arterial occlusive disease. Although prourokinase is quite stable in the plasma, it is prone to spontaneous cell-associated activation especially on the surface of endothelial cells.
Consequently therapeutic use of prourokinase has been limited to catheter delivery. As described in "Focus on CardioVascular Disease", a variant prourokinase has now been developed and may be suitable for systemic administration. Another field commonly associated with the cardiovascular system is the renin-angiotensin system. However in this edition of TherapeuticAdvances, angiotensin pathways are the subject of "Focus on CNS disease", spurred by a body of evidence describing how reduction of central angiotensin function has both antidepressant-like and anxiolytic-like actions. Evidence also exists in favor of a role of the renin-angiotensin system in learning and memory.
We finish off this overview of the current edition of TherapeuticAdvances by mentioning our two remaining focus sections. "Focus on Infectious Disease" highlights an interesting effect of retroviral agents. Drugs such as indinavir, lamivudine and zidovudine have traditionally been thought of as reverse transcriptase inhibitors, however recent evidence suggests that these molecules may also target host proteosomes. This could play an important role in toxicity, efficacy and drug resistance issues. On a different note, our LicensingOpportunities/Patent Update describes an exiting molecule under development by Innovative Vision Products. Cataract treatment is generally surgical, however the shear patient population size means that resources are outstripped and secondly, although the procedure is relatively safe a significant number of patients suffer complications. Innovative Vision Products have tackled this problem by developing an ophthalmic drug suitable for the non-surgical treatment of age-related cataracts. These two publications round off what we believe to have been yet another fascinating fortnight in the world of drug discovery.
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