Novel Heparanase Inhibitors for Cancer Therapy

用于癌症治疗的新型乙酰肝素酶抑制剂

• 批准号: 8018508
• 负责人: Ralph D Sanderson
• 金额: $ 33.39万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018508
• 关键词: Active Sites; Adverse effects; Affinity; Affinity Chromatography; Animal Model; Binding; Biological Assay; Biology; Bone Marrow; Carbohydrate Chemistry; Characteristics; Chemicals; Cleaved cell; Clinic; Clinical; Clinical Trials; Coagulants; Crystallization; Development; Disease; Docking; Dose; Drug Design; Drug Kinetics; Endoglycosidases; Enzymatic Biochemistry; Enzymes; Exhibits; Gelatinase B; Generations; Glycols; Goals; Growth; Growth Factor; Heparin; Heparitin Sulfate; Human; In Vitro; Institutes; Knockout Mice; Knowledge; Length; Link; Malignant Neoplasms; Methods; Modification; Molecular Models; Multiple Myeloma; Neoplasm Metastasis; Normal tissue morphology; Ohio; Oligosaccharides; Osteolysis; Osteolytic; PLAUR gene; Pathology; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phenotype; Play; Property; Proteins; Relative (related person); Research; Research Institute; Role; Scheme; Senior Scientist; Spectrometry; Structural Models; Structure; Structure-Activity Relationship; Testing; Therapeutic Studies; Translations; Up-Regulation; Uronic Acids; Vascular Endothelial Growth Factors; Vertebral column; Work; angiogenesis; antibody inhibitor; base; bone; cancer cell; cancer therapy; cancer type; density; design; drug candidate; drug development; enzyme activity; flexibility; heparanase; in vitro activity; in vivo; in vivo Model; inhibitor/antagonist; molecular modeling; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; preclinical study; public health relevance; research study; success; sulfation; three dimensional structure; tool; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The overall goal of the Sanderson Lab is to determine the role of the heparan sulfate / heparanase axis in regulating cancer and to use this knowledge to develop new anti-cancer therapies. The immediate goal of this project is to design and develop novel heparanase inhibitors to treat multiple myeloma. Heparanase, an endoglycosidase that cleaves heparan sulfate chains, is upregulated in many types of cancers and promotes an aggressive tumor phenotype. Heparanase is present in the bone marrow of many myeloma patients where high levels of the enzyme correlate with enhanced angiogenesis and poor prognosis. Using in vivo models, we have also shown that heparanase is a key driver of myeloma growth, osteolysis and metastasis. Together, these studies identify heparanase as a viable target for myeloma therapy and support our hypothesis that inhibitors of heparanase will block myeloma tumor growth and progression. In preliminary proof-of-principle studies, we have synthesized a chemically modified, non-anticoagulant heparin that acts as a potent inhibitor of heparanase activity in vitro and myeloma tumor growth in vivo. The goal of this project is to generate novel oligosaccharide and antibody inhibitors of heparanase that have characteristics favorable for their development as anti-myeloma drugs. To accomplish this we have assembled an interdisciplinary team of senior scientists having expertise in carbohydrate chemistry (Ronzoni Institute, Milan), heparanase biology and enzymology (Technion, Haifa), heparan sulfate/heparanase function in myeloma (UAB) and pharmacology and drug development (Ohio State). Aim 1 focuses on rational design of oligosaccharide inhibitors of heparanase enzyme activity; Aim 2 focuses on heparanase structural and molecular modeling studies that will enhance rational design of oligosaccharide inhibitors; Aim 3, using in vivo models of myeloma, will test the characteristics and efficacy of drug candidates developed in aim 1 with the goal of moving the most efficacious compounds toward clinical trials. These studies have potential for high impact by delivering new therapeutics for myeloma and perhaps other cancers and by providing new structural information on heparanase that will help unravel the mechanism of action of this important enzyme. PUBLIC HEALTH RELEVANCE: Heparanase is a protein made by cancer cells that plays a major role in helping them grow and spread throughout the body. This project is designed to develop new drugs that will block the function of heparanase and thereby block tumor growth and metastasis.

描述（由申请人提供）：桑德森实验室的总体目标是确定硫酸乙酰肝素 /肝素酶轴在调节癌症中的作用，并使用这些知识来开发新的抗癌疗法。该项目的直接目标是设计和开发新型的肝素酶抑制剂来治疗多发性骨髓瘤。肝素酶是一种裂解乙par硫酸盐链的内糖苷酶，在许多类型的癌症中被上调，并促进了侵袭性的肿瘤表型。肝素酶存在于许多骨髓瘤患者的骨髓中，其中高水平的酶与增强的血管生成和预后不良相关。使用体内模型，我们还表明乙par是骨髓瘤生长，骨溶解和转移的关键驱动力。总之，这些研究将肝素酶确定为骨髓瘤疗法的可行靶标，并支持我们的假设，即乙酰肝素酶抑制剂将阻止骨髓瘤肿瘤的生长和进展。在初步证明的研究中，我们合成了一种化学改良的非抗凝蛋白肝素，该化学改性肝素是体外体外和骨髓瘤肿瘤生长的有效抑制剂。该项目的目的是产生新型的寡糖和抗体抑制剂，它们具有有利于其作为抗肌瘤药物的特征。为此，我们组建了一个跨学科的小组，由高级科学家组成的碳水化合物化学专业知识（米兰的罗佐尼研究所），乙酰肝素酶生物学和酶学（Technion，Haifa），硫酸乙酰肝素/肝素酶在骨髓瘤（UAB）和药物学和药物学中（OHIO ohio）（ohio ohio）。 AIM 1专注于乙酰肝素酶活性的寡糖抑制剂的合理设计； AIM 2专注于肝素酶结构和分子建模研究，这些研究将增强寡糖抑制剂的合理设计； AIM 3使用骨髓瘤的体内模型，将测试AIM 1中开发的药物的特征和疗效，目的是将最有效的化合物转移到临床试验中。这些研究通过为骨髓瘤和其他癌症提供新的治疗剂，并提供有关肝素酶的新结构信息，从而有助于揭开这种重要酶的作用机制，从而具有高影响。 公共卫生相关性：肝素酶是一种由癌细胞生产的蛋白质，在帮助它们在整个体内成长和扩散方面起着重要作用。该项目旨在开发新药物，以阻断肝素酶的功能，从而阻止肿瘤生长和转移。