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BATON ROUGE, LA, United States

Patil S.A.,State University of New York at Buffalo | Bshara W.,Roswell Park Cancer Institute | Morrison C.,Roswell Park Cancer Institute | Chandrasekaran E.V.,Roswell Park Cancer Institute | And 3 more authors.
Glycoconjugate Journal | Year: 2014

Glycan structure alterations during cancer regulate disease progression and represent clinical biomarkers. The study determined the degree to which changes in glycosyltransferase activities during cancer can be related to aberrant cell-surface tumor associated carbohydrate structures (TACA). To this end, changes in sialyltransferase (sialylT), fucosyltransferase (fucT) and galactosyltransferase (galT) activity were measured in normal and tumor tissue using a miniaturized enzyme activity assay and synthetic glycoconjugates bearing terminal LacNAc Type-I (Galβ1-3GlcNAc), LacNAc Type-II (Galβ1-4GlcNAc), and mucin core-1/Type-III (Galβ1-3GalNAc) structures. These data were related to TACA using tissue microarrays containing 115 breast and 26 colon cancer specimen. The results show that primary human breast and colon tumors, but not adjacent normal tissue, express elevated β1,3GalT and α2,3SialylT activity that can form α2,3SialylatedType-IIIglycans (Siaα2-3Galβ1-3GalNAc). Prostate tumors did not exhibit such elevated enzymatic activities. α1,3/4FucT activity was higher in breast, but not in colon tissue. The enzymology based prediction of enhanced α2,3sialylated Type-III structures in breast tumors was verified using histochemical analysis of tissue sections and tissue microarrays. Here, the binding of two markers that recognize Galβ1-3GalNAc (peanut lectin and mAb A78-G/A7) was elevated in breast tumor, but not in normal control, only upon sialidase treatment. These antigens were also upregulated in colon tumors though to a lesser extent. α2,3sialylatedType-III expression correlated inversely with patient HER2 expression and breast metastatic potential. Overall, enzymology measurements of glycoT activity predict truncated O-glycan structures in tumors. High expression of the α2,3sialylated T-antigen O-glycans occur in breast tumors. A transformation from linear core-1 glycan to other epitopes may accompany metastasis. © 2014 Springer Science+Business Media New York. Source

Xie N.,Louisiana State University | Xie N.,Tumorend, Llc | Taylor C.M.,Louisiana State University
Journal of Organic Chemistry | Year: 2014

An efficient, convergent solution phase synthesis of monomer, dimer, trimer and tetramer of the β-l-arabinofuranosylated hydroxyproline (β-l-Araf-Hyp) glycocluster is described. This motif constitutes the carbohydrate-specific epitope of Art v 1, the major allergen of mugwort pollen. While a single monomeric unit was proposed at the outset, poor yields for the seemingly trivial steps of end-capping to replace protecting groups with N-terminal acetamides and C-terminal methyl amides led to the introduction of N-terminal, central and C-terminal β-l-Araf-Hyp building blocks. Dimer 2 was obtained in 60% yield by coupling of two monomers, followed by hydrogenolysis of benzyl ether protecting groups. Trimer 3 was obtained in 35% yield via a [2 + 1] coupling and tetramer 4 in 15% yield via a [2 + 2] fragment condensation. Circular dichroism spectra show that monomer 1 displays no organized structure, whereas compounds 2-4 show a strong negative band at 200 nm and a weak positive band at ∼220 mn, as is characteristic of the polyproline II helix. © 2014 American Chemical Society. Source

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 149.04K | Year: 2013

DESCRIPTION: We have preliminary data for a small molecule glyco-decoy that specifically side-tracks the biosynthesis of the ligand for E-selection, and is a candidate for a novel anti-inflammatory. The three members E, L and P of the selection family areinflammatory adhesion molecules expressed constitutively on the surface of blood leukocytes and on activated endothelial cells and platelets. Discoveries of glycans sialyl LeX and sialyl Lea as mucin glycoprotein ligands for the selection family of cell adhesion proteins has stirred immense interest in pursuit of small molecules for treatment of inflammatory, vascular and cancer diseases. The underlying premise is that controlling the rate of leukocyte adhesion by antagonizing selectin-ligand interactions can lead to new therapies to combat these diseases. GlycoMimetics, Inc., has licensed a selectin ligand derivative to Pfizer in 2011 for 340M with the first indication sickle cell inflammation, as an example of the newly perceived commercial value in thisarea. We took a different approach, focusing on specificities of sets of enzymes that construct the native ligands. Among PSGL1, E selection and L selection, the latter is known to bind sulfated mucin-glycans. Our findings led to the discovery of sulfo-LeX, sulfo-Lea and various core 2 (Galss3 [Galss4GlcNAcss6]GalNAc ) glycans as the ligands for these cell adhesion proteins. In another approach, we focused on synthesis of modified analogs of monosaccharides such as 4-fluoro-GlcNAc acetates and 4-fluoro-GalNAc acetates as cell-penetrating metabolic inhibitors of the selection ligand assembly enzymes. We also synthesized small molecules as glyco-decoys to disrupt biosynthesis of natural ligands of these selections. A small synthetic glyco-decoy competes with the natural acceptor-substrate and thus diverts the synthesis of the glycan chains from endogenous glycoproteins and glycolipids to soluble ligands, which act as inhibitors of selection binding to cell-bound ligand. Secondarily, ligand absence on cell-boundmolecules in the presence of the glyco-decoy precludes adhesion events that begin the inflammatory process. The underlying theme of this strategy is that biosynthetic knowledge about specificity of key enzymes as hits is a compelling requirement for developing small molecules for therapeutic discoveries based on inhibiting selection adhesion systems. We have examined specificity of enzyme assembly of N-glycan ligands for E selections. Preliminarily, we have discovered a novel compound that disrupts the biosynthesis of glycans for E selections (patent submitted). In Phase I, the prime objective is to synthesize analogs and related compounds and test as inhibitors of E selection ligand biosynthesis in HL60 cells. CD44 is endowed with a ligand for E selection, and also has a specific receptor for hyaluronic acid, promoting migration in normal cells. CD44 is highly expressed in various cancer cells. A small molecule inhibiting biosynthesis of E selection-specific N-glycans such as in CD44 brings new potentialtools for mitigation of inflammatory disorders and adhesion events in cancer. This Phase I proposal meets the central tenet of the SBIR program for promising commercial products. PUBLIC HEALTH RELEVANCE Narrative In our work on biosynthesis of glycans andthe assembly enzyme specificities, we have found a small molecule glyco-decoy that specifically disrupts ligand synthesis for E selectin. This preliminary result foretells a whole potential set o compounds and derivatives as drugs that are cell-penetrating and can side-track biosynthetic pathways leading to inflammatory cell adhesion ligands. This has a potential application in many inflammatory diseases including cardiovascular, arthritic and cancer where adhesion molecules can play a role in migration and metastasis.

Tumorend, Llc | Date: 2009-03-13

Cardiovascular pharmaceuticals; Dermatological pharmaceutical products; Pharmaceutical preparations and substances for the treatment of viral, metabolic, endocrine, musculoskeletal, cardiovascular, cardiopulmonary, genitourinary, sexual dysfunction, oncological, hepatological, ophthalmic, respiratory, neurological, gastrointestinal, hormonal, dermatological, psychiatric and immune system related diseases and disorders; Pharmaceutical preparations for the prevention and treatment of disorders of the nervous system, the immune system, the cardio-vascular system, the metabolic system, the respiratory system, the musculo-skeletal system, the genitourinary system; for the treatment of inflammatory disorders; for use in dermatology, oncology, hematology and in tissue and organ transplantation, in ophthalmology and for gastroenterological disorders; Pharmaceutical preparations for the treatment of tumors, burns, spinal cord injury; Pharmaceutical preparations for use in dermatology; Pharmaceutical preparations for wounds.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 150.00K | Year: 2012

DESCRIPTION (provided by applicant): CM101 is a polysaccharide tumor angiogenesis-targeting, complement activating, immune stimulating biological produced fermentatively from Group B Streptococcus. CM101 binds a capillary endothelium receptor, HP59, causing inflammatory cytokine cascades, recruiting CD69+ granulocytes to destroy neovasculature and surrounding tumor. This SBIR proposal is to determine Structure-Activity-Relationship (SAR) for CM101 to identify angiogenesis-specific HP59-targeting mechanismsand establish minimal active molecular structure (pharmacophore). CM101 is not an angiogenesis inhibitor like Avastin and related biologicals and drugs, but has a completely different mechanism of action, stimulating immune attack on HP59+ tumor neovasculature. CM101 is a promising active pharmaceutical ingredient (API) biological for cancer therapy in results from animal studies and a human Phase I safety trial published in 1997. More recent intellectual property for CM101 purification and the HP59 receptor now protects products through 2026-2028. CM101 development was interrupted by previous business failures, despite the promising technology. By establishing the pharmacophore, pinpointing biochemical binding interaction with the tumor capillary endothelium lectin receptor HP59 (See Wikipedia), we will discover mechanism of action details, new composition of matter intellectual property, and potential for development of small drug pipelines, to stimulate investors and major pharmaceutical companies' incentive to support planned Phase I/II clinical trials. In sum, CM101, the Group B Streptococcal Toxin (GBS-Toxin) is a 270Kda polysaccharide exhibits targeted binding to HP59, a specific tumor cell endothelial cell surface lectin, therefore a highly specific tumor vasculature targeting biological therapeutic, needing SAR for development. PUBLIC HEALTH RELEVANCE: This SBIR grant proposal seeks to determine the Structure-Activity-Relationship for CM101, a tumor neovasculature targeting Group B Streptococcal toxin that binds the lectin tumor angiogenesis marker HP59. HP59 binding by CM101 results in complement activation and subsequent inflammatory response against the tumor, which has been published in animal and human Phase I trials. We intend to molecularly identify the HP59 targeting mechanism, to define mechanism of action, to establish updated intellectual property, and provide potential drug pipelines by identification of a minimum pharmacophore for HP59 binding and for complement activation.

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