TherapeuticAdvances is up-dated twice-monthly highlighting 100's novel projects ready for development and commercialization.

January-December 2002

Target of the Month:  

• BMS-191095, a K(ATP) channel opener with improved cardioprotective properties

• Survivin as a target for cancer therapy

• GSK-3: A target for Alzheimer's disease

• Melatonin: An emerging target for multiple conditions

• Stat5: A target for immunological and neoplastic disease

• Protein kinase D: A signalling molecule with multiple therapeutic implications

• Leptin: a target for a growing list of conditions

• The interleukin-10 family of cytokines

• Serotonin 5-HT7 receptor antagonists as candidate migraine therapies

• PLA2, an unexploited target for inflammation and infectious diseases

• Hemostasis modulators: The next generation of anticancer molecules? 

• GSK-3 inhibitors for diabetes, Alzheimer's disease, stroke and manic depression

• The broad based therapeutic potential of PARP-1 inhibitors

• Mixed kappa opioid/somatostatin ligands as treatments for cancer progression and pain

• Protecting against Alzheimer's disease with Humanin

• Endostatin as a lead anti-angiogenic treatment

• Histone deacetylase inhibitors: An emerging class of anti-cancer drugs

Target "Lifestyle"

• CD40: A novel target for the prevention of bone loss

• LXA4 mimics as asthma therapies

• Female arousal disorder

• YM358: An AT1 receptor antagonist for the prevention and treatment of myocardial infarction

• The growing world of sexual dysfunction: From erectile dysfunction to premature ejaculation?

Focus on Targeted Cancer Therapy:  

• Metastatic control by histone deacetylase inhibitors

• Cathepsin-D: A novel approach to breast cancer

• ET(A) receptor antagonists as anti-cancer agents

• Radioligand therapy: Targeting tumors with labeled lanreotide

• Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy.

• Survivin a candidate for cancer-specific apoptotic- and immuno-therapies

• Camel antibody fragments for improved cancer immunotherapy

• Trastuzumab as a treatment for lung cancer?

• Specific activation of chemotherapeutic prodrugs in the tumor milieu

• Immunotherapeutic targeting of P-glycoprotein

• Virosome technology drives forward the fight against cancer

• Improvement to immunotherapy made possible through modified ricin toxin

Focus on Airway disease:  

• Novel approaches to cystic fibrosis

• Breakthroughs in cystic fibrosis?

• LXA4 mimics as asthma therapies

• Histone acetylation: A target for asthma

• ADAM33: A novel target for asthma

• STAT6: A key pathological target for localized treatment of asthma

• MMP-9 as a target for COPD

• Increased expression of the human Ca2+-activated Cl- channel 1 (CaCC1) gene in the asthmatic airway.

• CD44 mimics as candidates for the treatment of asthma

• Novel inhibitors of cell adhesion for the treatment of asthma

• NVP-ABE171, a selective PDE4D inhibitor for the treatment of airway inflammatory disease

• CCR3 antagonists for the treatment of allergy

• Galectin 14, a novel galectin with potential as an asthma target

• IL-18 antagonists as therapies for acute airway inflammation

• IL-13 blockade as a therapeutic intervention for asthma

• Experimental models of COPD: A critical review

• Ecalectin: a novel eosinophil-activating factor

Focus on Oncology:  

• EphA2 ligands as specific inhibitors of tumor angiogenesis

• Cathepsin-D: A novel approach to breast cancer

• Unleashing the therapeutic potential of maspin

• Chromatin methylation: An approach to gene silencing

• Targeting Critical Regions of Genomic DNA with DNA-Damaging Agents 

• Novel histone deacetylase inhibitors

• Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells.

• Preventing the attachment of metastatic cells to distant vasculature

• Novel Sulindac derivatives as candidate anti-cancer drugs

• Bisphosphonates prevent tumor progression as well as metastatic bone destruction

• Targeting platelets in the treatment of cancer

• An anti-metastatic non-toxic tetracycline derivative

• Mixed kappa opioid/somatostatin ligands as treatments for cancer progression and pain

• IL-6 induces multidrug resistance in breast cancer

• Reversing resistance to chemotherapy

• CLN3 boosts ceramide production with dramatic anti-cancer activity

Focus on CardioVascular disease:

• DPC423, a selective inhibitor of factor Xa for the treatment of thrombotic diseases

• Microplasmin as an improved treatment of stroke

• PAR-2: A therapeutic target for limb ischemia

• The role of angiotensin in ischemic stroke

• Angiotensin II receptor antagonists prevent atherosclerosis

• YM358: An AT1 receptor antagonist for the prevention and treatment of myocardial infarction

• Treatment of peripheral vascular disease with rFGF-2

• Fractalkine receptor antagonists: Novel approaches to stroke

• NCX4016 (NO-aspirin) reduces infarct size and suppresses arrhythmias following myocardial ischaemia/reperfusion in pigs.

• Neuroserpin as a candidate neuroprotective in the treatment of stroke

• Prourokinase variants as improved thrombolytics

• The therapeutic opportunities of targeting MCP-1

• P2 receptors: new potential players in atherosclerosis

• FR183998 inhibits Na+/H+ exchange and IL-8 accumulation following cardiac ischemia

• Cardiovascular risks of canabinoid receptor antagonists

• Ezetimibe prevents the development of artherosclerosis 

• Identification of relaxin receptors

• Expanding the possible indication of erythropoietin from anemia to CNS disease

Focus on Metabolic Diseases:

• GSK-3 inhibition as a strategy for improving glucose handling in diabetes

• Modulating insulin receptor phosphorylation as a treatment for diabetes

• PMT13, a novel PPARgamma agonist for the treatment of diabetes and obesity

• Endothelin as a factor underlying insulin resistance

• The link between diabetes and erectile dysfunction

• SREBP-1: A target for insulin resistance

• Advances in the development of insulin analogues

• Failure of eating to trigger ghrelin reduction in obesity

• Acute effect of L-796568, a novel beta 3-adrenergic receptor agonist, on energy expenditure in obese men.

• Advances in artificial insulin secreting cells

• DGAT1, a target for obesity and diabetes

• Exploiting the anorectic and insulin sensitizing activity of endogenous leptin

• Improved targets for diabetic retinopathy

• Adenosine A1 receptor agonists as inhibitor of insulin resistance

• Targeting the link between aging and obesity

• Leptin uptake by the brain

Focus on Immunology & Inflammatory disease:

• Peripheral benzodiazapine receptors as a target for rheumatoid arthritis

• CD200Fc, a treatment for autoimmune disease

• Rho inhibitors for the blockade of IL-8 release during inflammatory disease?

• MCC-478: a promising new anti-HBV agent

• Endomorphins: Improved analgesia and anti-inflammatory molecules

• Capsiates: Anti-inflammatory activity without VR1 binding

• PDE4 inhibitors for the treatment of atopic dermatitis

• Effective therapy of Crohn's disease

• A novel peptide derivative exhibits anti inflammatory and antioxidant activity in adjuvant induced arthritis in rats.

• Treatment of IBD through selective prostaglandin receptor agonists?

• A novel CsA receptor (cyclophilin) ligand with exciting anti-inflammatory activity

• Angiogenesis inhibitors for the treatment of arthritis

• Misoprostol enhances the analgesic activity of NSAIDs

• Improved anti-inflammatory PDE IV inhibitors

• A novel delta opiate receptor antagonist for autoimmune disease

• MAPK inhibitors as novel treatments for Crohn's disease

• NSAIDs vs COX-2 inhibitors for osteoarthritis

• Novel roles of p-glycoprotein

Focus on Functional Genomics:  

• Novel targets for metastatic/invasive lung cancer

• Improved technology for identifying SNPs

Focus on infectious disease:  

• Anti-viral activity of the HIV-1 candidate, L-870812

• Emerging indications for histone deacetylase inhibitors: fungal infection

• Benzodiazapines as anti-malarials

• Therapeutic approaches to respiratory tract viruses

• Reducing HIV infectivity

• Antiviral activty of cyclin dependent kinase inhibitors

• Role of lipoteichoic acid in infection and inflammation.

• Targeting host cellular machinery to prevent HIV-1 infection

• Antiretrovirals target host proteosomes

• Kappa opioid ligands as underexploited treatments of HIV-1 infection

• Anti-viral protease inhibitors offer hope for the treatment of cancer

• Novel therapies for the treatment of malaria

• New antiviral for the treatment of hepatitis B virus infection

• RWJ-270201, a once daily treatment of influenza

• Sigma 2 receptor agonists as novel anticancer treatments

Focus on Pain

• BDNF receptor antagonists as anti-nociceptives

• Orexin as a target for pain

• Modulators of VR1: A novel approach to analgesia

• HSP90 modulated VR1 function

Focus on Assay Technology: 

• Clinically predictive screens for cystic fibrosis, IBD, IBS and diarrhea

• HTS assays for cytotoxic molecules

• HTS assays of apoptosis

Focus on CNS Disease: 

• Novel apomorphine analogues as candidate treatments of Alzheimer's disease

• Leptin receptor activation plays a role in memory function

• Clusterin as a target for Alzheimer’s disease

• Identifying new targets for the treatment of cognitive dysfunction

• Further insights into antidepressant activity of NK-1 antagonists

• Novel dual 5-HT1A antagonists/SSRI activity 

• Selective and effective target for novel analgesics

• Treating spinal cord injury

• Eliminating membrane depolarization caused by the Alzheimer peptide A(1-42, aggr.) 

• Neuroprotection through the blockade of proteolytic activation of t-PA

• The renin-angiotensin system as a target for Alzheimer's and affective disorders

• Novel beta sheet breakers as candidates for Alzheimer's disease

• Improving spatial memory deficit following stroke

• Novel VR1 antagonists

• Selecting candidates for Alzheimer's disease from a library of NSAIDs

• Proteomic analysis of Alzheimer's disease

• Human kallikrein 6 as a target for multiple CNS diseases

Focus on Angiogenesis: 

• Novel approaches to cardiovascular disease

• ZD6474, a VEGF-2 receptor antagonist for the treatment of cancer

• Bisphosphonates are inhibitors of angiogenesis

• GSK-3 inhibitors as stimulators of angiogenesis

• New approaches to VEGF blockade

• ANO-2: A novel inhibitor of angiogenesis

• Mu opioid receptors may increase tumor progression

• New anti-angiogenic shark cartilage derivatives

• Angiogenic factors in endometriosis.

• HIF-1 and tumor progression: pathophysiology and therapeutics

• Targeting chemotherapeutics to tumor vasculature

• Targeted thrombosis as an effective treatment of cancer

• Targeting hematasis in the treatment of cancer

• Lmo2 as a novel anti-angiogenic target

• Available assays for angiogenesis inhibitors

• Breakthrough in the search for treatments of cancer and spinal cord injury

• Oltipraz, a candidate antiangiogenesis molecule

Focus on Metastasis: 

• ZD6474, a VEGF-2 receptor antagonist for the treatment of cancer

• Hypoxia increases uPAR expression and invasiveness of breast cancer cells

• COX-2 inhibitors: Growing interest in anti-cancer activity

• SHPS1: A promising target for the prevention of metastasis

• Lymphangiogenesis: A key player in metastasis?

• Laminin gamma 1 chain peptide, C-16 (KAFDITYVRLKF), promotes migration, MMP-9 secretion, and pulmonary metastasis of B16-F10 mouse melanoma cells.

• Osteopontin: The target of choice for prevention of metastasis?

• Ornithine decarboxylase as an underexploited anticancer target

• Anti-cancer effects of FTY720

• Anti-angiogenic activity of SR 25989

• S100A4, a target for metastatic cancer

• Antibody and oligonucleotide inhibitors of angiogenein that reduce the growth and metastasis of breast and prostate cancer

• Neovastat as a treatment of metastatic breast cancer

• Osteopontin as a target for cancer metastases

Focus on Cell Death:

• Death-associated protein kinase (DAP-kinase) as a target for stroke

• GSK-3 mediates the neurotoxic effects of beta-amyloid

• Targeting apoptosis as a treatment of stroke

• The impact of P-glycoprotein and MRP expression on SCLC response

• MMP-9 nitrosylation: A role in neurodegenerative diseases and stroke

• STATs: Key components of the apoptosis cascade

• Apoptosis in the treatment of rheumatoid arthritis

• Reversing tumor drug resistance

• Identification of inhibitor-of-differentiation 2 (Id2) as a modulator of neuronal apoptosis.

• Histone deacetylase inhibitors as pro-apoptotic candidates

• Predicting p-glycoprotein inhibitors

• A Novel activator of apoptosis

• Apoptosis targets for pancreatic cancer

• Apicidin induces the expression of fas/fas ligand by cancer cells

• Prostate cancer specific derivatives of thapsigargin

• Sigma 2 receptor agonists as novel anticancer treatments

Licensing Opportunities/Patent Update:  

• Hypoxia increases uPAR expression and invasiveness of breast cancer cells

• Identifying new targets for the treatment of cognitive dysfunction

• CD40: A novel target for the prevention of bone loss

• Therapeutic activity of high density lipoproteins

• PPAR ligands prevent and limit the damage caused by myocardial infarction

• PlGF a key target for the modulation of angiogenesis

• IL-15: therapeutic potential in metabolic and immunological disorders

• A new family of thromboxane receptor antagonists with secondary thromboxane synthase inhibition.

• Novel integrase inhibitors as HIV-1 treatments

• Pharmaceutical approaches to cataract

• Vitamin E analogues: improved treatment of cardiovascular and neoplastic disease

• Targeting HP59: Effective blockers of tumor specific angiogenesis

• Improved use of fish oils in the effective treatment of autoimmune disease

• Virosome technology drives forward the fight against cancer

Focus on industrial development:  

• The emergence of vasopressin receptor antagonists

• HSP90 modulated VR1 function

• ONO-6818, neutrophil elastase inhibitor as a candidate treatment of COPD

• BMS-191095, a K(ATP) channel opener with improved cardioprotective properties

• Neuregulin 1: A target for schizophrenia

• Angioarrestin: A novel angiopoietin-like molecul

• SNAP-7941, a candidate Antidepressant, anxiolytic and anorectic 

• Ro 28-2653, an MMP inhibitor with anti-cancer activity

• Nonpeptide inhibitors of cathepsin G: optimization of a novel beta-ketophosphonic acid lead by structure-based drug design. 

• Dual TACE/MMP inhibitors as candidate therapies for asthma and COPD

• Potential of AnoMED's CxCR4 antagonist AMD-3100 in asthma treatment

• Dual topoisomerase I and II inhibitors from Xenova as improved anticancer drugs

• Antithrombotic activity of human anti-factor IX/IXa antibody

• Improved anticoagulants

• Follow up molecules to the anti-depressant/anti-emetic NK1 antagonist, MK869

• Osanetant enters phase IIb development as an NK3 antagonist

• MAP kinase inhibitors: A state of the art

• New options for NSAID-related GI injury