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Emerging Drug Discovery Targets:4th April 2003

Posted on: 03 Apr 03


This week
TherapeuticAdvances: 27th February 2003


Emerging Drug Discovery Targets

from LeadDiscovery

4th April 2003


In this weeks edition:

  • Blocking elastase activity: A therapeutic option for the treatment of COPD and myocardial infarction [more]
  • ATN-161, an antiangiogenic and antitumor integrin antagonist (license opportunity) [more]
  • Emerging targets for obesity and diabetes [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]:
    • Therapeutic & pharmaceutical opportunities for osteoporosis and atherosclerosis
    • Guide to the European Life Science Venture Capital Market

"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

Please feel free to distribute "Emerging Drug Discovery Targets" to your colleagues or arrange for it to be accessed through your company intranet.

Blocking elastase activity: A therapeutic option for the treatment of COPD and myocardial infarction: There is a pressing need to develop new treatments for the chronic obstructive pulmonary diseases (COPD), chronic obstructive bronchitis and emphysema. World-wide, 600 million people suffer from COPD, with some three million dying from the disease each year. This serious healthcare problem is paralleled by a global pharma market of US$2.8 billion. There is a particular need to develop drugs that control the underlying inflammatory and destructive processes that cause COPD as no currently available drug therapy reduces the relentless progression of COPD. In contrast to the enormous advances made in asthma management little significant progress has been made in COPD therapeutics.

In our recent analysis of COPD, produced in collaboration with field-leader Peter Barnes, we highlight the clinical needs and pharmaceutical development surrounding COPD and review emerging pharmaceutical targets (click here for dossier access). One target addressed was the proteases. There is compelling evidence for an imbalance between proteases that digest elastin (and other structural proteins) and antiproteases that protect against this as a cause of COPD. This suggests that inhibiting these proteolytic enzymes may be beneficial and theoretically should prevent the progression of airflow obstruction in COPD. Reversing airway damage may be of even greater therapeutic use and the target that has received the greatest attention in this respect is the retinoic acid receptor.

We have analyzed the therapeutic and pharmaceutical potential of the retinoids in a recent DiscoveryDossier (Click here to access). With respect to COPD, retinoic acid increases the number of alveoli in developing rats and, remarkably, reverses the histological and physiological changes induced by elastase treatment of adult rats.

Most recently, Japanese researchers have shown that retinoic acid prevents the ability of elastase to reduce the viability of human airway cells. The pro-apoptotic effect of elastase was also reduced. Retinoic acid may, therefore, have both protective and curative effects in the context of COPD [more on these findings]

In addition to being of potential use in the treatment of COPD, elastase inhibitors are also expected to limit tissue damage following myocardial infarction. This concept is supported by a second recent study published by researchers at Sanofi-Synthelabo showing that SSR69071, a potent (0.02nM) inhibitor of elastase, reduced cardiac infarct size when administered before ischemia or just prior to reperfusion in an animal model of myocardial infarction [more on these findings]

Despite their therapeutic role in at least two major and unmet therapeutic fields, few elastase inhibitors, especially small molecule elastase inhibitors, are in development. In this respect readers may be interested to know about LeadDiscovery's PharmaceuticalSolutions service which offers expert input both on target conceptualization as well as library design and screening around selected targets [click here for more information on this service].


ATN-161, an antiangiogenic and antitumor integrin antagonist (license opportunity):  Angiogenesis, the formation of new blood vessels, is crucial to tumor progression. Beta integrins, including beta(1), beta(3) and beta(5) subtypes, are present on endothelial cells and mediate endothelial cell-extracellular matrix interactions. Of particular interest to cancer progression is integrin alpha(5)beta(1) which is expressed on activated endothelial cells and plays a critical role in tumor angiogenesis. Likewise alpha(5)beta(1) integrin is also present on many tumor cells where it plays a key role in adhesion and migration and hence blocking this integrin can affect tumor progression both directly and also indirectly through the prevention of angiogenesis. We highlight a study recently reported by researchers at the M. D. Anderson Cancer Center in collaboration with the San Diego-based pharmaceutical company, Attenuon. Results show that the integrin alpha(5)beta(1) antagonist, ATN-161 in combination with 5-FU diminished liver metastases of murine colon cancer cells both with respect to tumor burden and the number of metastases. Liver tumors in the ATN-161 and ATN-161+5-FU groups had significantly fewer microvessels than tumors in the control or 5-FU-treated groups. Unlike treatment with either agent alone, ATN-161+5-FU significantly increased tumor cell apoptosis and decreased tumor cell proliferation and improved overall survival. Hence ATN-161 effectively reduced tumor angiogenesis and furthermore it also enhanced the antineoplastic activity of 5-FU. The addition of non-cytotoxic cancer therapeutics such as ATN-161 that target both the tumor vasculature and the cancer cells themselves to commonly employed chemotherapeutic strategies may be a promising approach for treating metastatic colorectal cancer. Since the expression of alpha(5)beta(1) integrin by cancer cells and the role of this molecule in tumor angiogenesis extends across a range of different cancers, the therapeutic benefit of ATN-161 is expected to extend past colorectal cancer. An alpha(v)beta(3) antagonists has been used with considerable success in an animal model of rheumatoid arthritis. Despite the fact that beta(1) integrins are highly expressed on RA synovial fluid lymphocytes, as well as synovial tissue lining cells, leukocytes, fibroblasts and endothelia the effects of an alpha(5)beta(1) have yet to be reported. ATN-161 therefore deserves further study in models of arthritis as well as cancer [more on these findings]


Emerging targets for the treatment of obesity and diabetes: The identification of new targets for obesity therapeutics represents a key priority for the pharmaceutical industry. This has been driven by the large and growing numbers of obese individuals around the world, the high incidence of serious co-morbidities such as insulin resistance and diabetes, and a market predicted to reach $3.7 billion by 2008. Obesity occurs when calorific intake exceeds energy expenditure. LeadDiscovery has recently analyzed two emerging anti-obesity targets, ghrelin which regulates food intake (click here for more), and the retinoids which also plays a role in both food intake as well as energy expenditure (click here for more). Leptin has also received considerable interest with respect to obesity. Leptin is released into the blood from fat cells and circulates to the brain where it crosses the blood-brain barrier to act at receptors within the central nervous system. Leptin inhibits food intake, reduces body weight and stimulates energy expenditure. Leptin expression increases after food intake and decreases during fasting. Reduced expression has been shown to evoke insulin resistance, while a leptin agonist has recently been shown to not only reduce body weight and glucose levels in obese animals but also to increase insulin sensitivity. Despite the promise that leptin agonists may have for the treatment of both diabetes and obesity, such molecules have only met with limited success in clinical trials. This lack of effect has been suggested to result from the development of leptin resistance. Various different mechanisms of leptin resistance have been proposed including a defect in the transport of leptin across the blood-brain barrier. This suggests that strategies that may increase hypothalmic leptin expression may overcome resistance and hence reduce obesity. University of Florida researchers have recently confirmed this hypothesis by showing that gene transfer of the leptin gene into the brain prevented aging-associated increase in body weight and adiposity in adult rats for 6 months of the experiment. In addition, obesity was prevented in rats introduced to a high-fat diet and also reversed in obese-prone rats maintained on a high-fat diet. Body weight homeostasis and loss of adiposity by leptin gene therapy was achieved by an increase in energy expenditure, and a voluntary reduction in food intake was also reported. Importantly, this therapy reduced blood levels of insulin, triglycerides and free fatty acids, the pathophysiologic correlates of insulin resistance. This study therefore makes the important conclusion that developing strategies to increase leptin levels in the brain could offer a diabetes/obesity treatment option [more on these findings]

A second therapeutic target for the treatment of insulin resistance is glycogen synthase kinase-3 (GSK-3). A recent report produced by LeadDiscovery analysts under the editorial guidance of field-leader, Dr Hagit Eldar-Finkelman, offers a state of the art overview of GSK-3 analyzing the therapeutic role of inhibitors of this enzyme (click here for access). The support for targeting GSK-3 as a treatment of diabetes arises from the ability of this enzyme to negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. Glycogen synthase appears to be the rate-limiting step for glycogen synthesis, at least in the liver, and it has been shown that GSK-3 inhibition increases liver glycogen synthesis. This improved glucose handling in Zucker diabetic fatty rats, lowering fasting hyperglycemia. Likewise GSK-3 inhibitors stimulated glucose incorporation into glycogen in cultured human skeletal muscle cells. GSK-3 has also been shown to phosphorylate IRS-1, which in turn attenuates insulin signaling however a limited amount of information is available regarding the utility of highly selective inhibitors of GSK-3 for the modification of insulin action under conditions of insulin resistance. Researchers at Chiron, who have developed the field-leading GSK-3 inhibitors CT98014 and CHIR98023 researchers have recently demonstrated that their molecules activate glycogen synthase in cultured CHO cells transfected with the insulin receptor; in primary hepatocytes; and in isolated type 1 skeletal muscle of both lean Zucker and ZDF rats. Of note, these GSK-3 inhibitors enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or markedly elevating insulin. Collectively, these results represent a major advance in the development of GSK-3 inhibitors for the treatment of the insulin resistance of type 2 diabetes. Not only do these results offer further convincing evidence relating to the concept of developing GSK-3 inhibitors for this condition but they also strongly support the further development of Chiron’s therapeutic candidates [more on these findings]

Readers involved in the development of this therapeutic area should be aware of the “Kinase Enterprise Library” recently highlighted by LeadDiscovery. This library represents a highly targeted collection of molecules expanded from a diverse collection of kinase inhibitor templates. The library is ready for screening for inhibitors of GSK-3 (click here for further information).


Advances from industry (20th March - 2nd April)

  • Enfuvirtide: The US FDA has approved the use of Roche and Trimeris’ fusion inhibitor, enfuvirtide (FUZEON), as a therapy for HIV-1 infection in combination with other antiretrovirals in treatment- experienced patients. This follows the submission of an NDA in September 2002 and a six-month Priority Review by the US FDA. Approval is being awaited in the EU, Australia, Canada and Switzerland for this indication.
  • Aprinocarsen: Isis and Lilly reported phase III data for aprinocarsen sodium (AFFINITAC), an antisense oligonucleotide against protein kinase C-alpha being developed for the treatment of cancer. The trial enrolled 616 patients with advanced nonsmall cell lung cancer (NSCLC) who were treated with either aprinocarsen sodium plus standard chemotherapy of carboplatin and paclitaxel, or standard chemotherapy alone. Results demonstrated no significant difference in overall survival of patients treated with only standard chemotherapy (median survival 9.7 months) compared with those treated with chemotherapy plus aprinocarsen sodium (median survival 10 months). There was no increase in severe toxicities or toxicity-related deaths in patients receiving aprinocarsen sodium compared with those receiving standard chemotherapy alone. The most commonly reported side effects associated with aprinocarsen sodium were fatigue and nausea; patients treated with the antisense agent also experienced a higher incidence of moderate thrombocytopenia, nausea and vomiting.
  • ATN-161: As described above, Attenuon have reported preclinical data for their integrin alpha(5)beta(1) antagonist, ATN-161. This therapeutic candidate has been shown to target both the tumor vasculature, effectively reducing angiogenesis, and cancer cells themselves. In a recent study ATN-161 was shown to limit the vascularization of metastatic colon cancer and to enhance the antineoplastic activity of 5-FU. ATN-161 may have additional activity in rheumatoid arthritis and represents a licensing opportunity [more on these findings]
  • SSR69071: Also as described earlier, Sanofi-Synthelabo report preclinical data on their elastase inhibitor, SSR69071. This molecule reportedly demonstrates activity in models of airway inflammation and also reduces cardiac infarct size in a model of myocardial infarction [more on these findings]
  • E5564: Eisai's second-generation synthetic lipodisaccharide, E5564 inhibits LPS-mediated activation of inflammatory cells and has been reported to block the ability of Gram negative bacteria to stimulate human cytokine production in whole blood. E5564 also prevents the induction of LPS-induced cytokines and LPS or bacterial-induced lethality in primed mice. Most recently phase I studies have demonstrated that E-5564 reduces the systemic effects of LPS in human volunteers. E5564 has now entered phase II evaluation [more on these findings]
  • BAY 41-2272: Bayer's BAY 41-2272 is a novel non-NO-based direct stimulator of soluble guanylyl cyclase. In a recent study, BAY 41-2272 was administered to conscious rabbits and was reported to effectively induce penile erections but only in the presence of a nitric oxide donor. It is therefore expected that BAY 41-2272 would have proerectile activity and that, like sildenafil, this effect would predominate during endogenous during sexual arousal [more on these findings]

New DiscoveryDossiers:

  • Therapeutic & pharmaceutical opportunities for osteoporosis and atherosclerosis [More]
  • Guide to the European Life Science Venture Capital Market [More]


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

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