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: 8600889
• 负责人: Ralph D Sanderson
• 金额: $ 35.24万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8600889
• 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.

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/乙酰肝素酶轴在调节癌症中的作用，并利用这些知识开发新的抗癌疗法。该项目的近期目标是设计和开发新型乙酰肝素酶抑制剂来治疗多发性骨髓瘤。乙酰肝素酶是一种裂解硫酸乙酰肝素链的糖苷内切酶，在许多类型的癌症中表达上调，并促进侵袭性肿瘤表型。许多骨髓瘤患者的骨髓中都存在乙酰肝素酶，其中高水平的酶与血管生成增强和预后不良相关。使用体内模型，我们还表明乙酰肝素酶是骨髓瘤生长、骨质溶解和转移的关键驱动因素。总之，这些研究确定乙酰肝素酶是骨髓瘤治疗的可行靶点，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。在初步的原理验证研究中，我们合成了一种化学修饰的非抗凝肝素，它可以作为体外乙酰肝素酶活性和体内骨髓瘤肿瘤生长的有效抑制剂。该项目的目标是产生新型乙酰肝素酶寡糖和抗体抑制剂，这些抑制剂具有有利于其开发为抗骨髓瘤药物的特性。为了实现这一目标，我们组建了一个由资深科学家组成的跨学科团队，他们在碳水化合物化学（米兰龙佐尼研究所）、乙酰肝素酶生物学和酶学（以色列理工学院，海法）、硫酸乙酰肝素/骨髓瘤中的乙酰肝素酶功能（UAB）以及药理学和药物开发方面拥有专业知识（俄亥俄州）。目标1侧重于合理设计乙酰肝素酶活性的寡糖抑制剂；目标 2 侧重于乙酰肝素酶结构和分子建模研究，这将增强寡糖抑制剂的合理设计；目标 3 将使用骨髓瘤体内模型来测试目标 1 中开发的候选药物的特性和功效，旨在将最有效​​的化合物推向临床试验。这些研究有可能产生巨大影响，为骨髓瘤和其他癌症提供新的治疗方法，并提供有关乙酰肝素酶的新结构信息，这将有助于揭示这种重要酶的作用机制。

项目成果

Sulfated hexasaccharides attenuate metastasis by inhibition of P-selectin and heparanase.

硫酸化六糖通过抑制 P-选择素和乙酰肝素酶来减弱转移。

• DOI: 10.1593/neo.101734
• 发表时间: 2011-05-01
• 期刊: Neoplasia
• 影响因子: 4.8
• 作者: L. Borsig;I. Vlodavsky;R. Ishai‐Michaeli;G. Torri;E. Vismara
• 通讯作者: E. Vismara

Anti-metastatic semi-synthetic sulfated maltotriose C-C linked dimers. Synthesis and characterisation.

抗转移半合成硫酸化麦芽三糖 C-C 连接二聚体。

• 发表时间: 2012-08-17
• 作者: Vismara, Elena;Coletti, Alessia;Valerio, Antonio;Naggi, AnnaMaria;Urso, Elena;Torri, Giangiacomo
• 通讯作者: Torri, Giangiacomo

Re-visiting the structure of heparin.

重新审视肝素的结构。

• DOI: 10.1016/j.carres.2014.06.023
• 发表时间: 2015-02-11
• 期刊: Carbohydrate research
• 影响因子: 3.1
• 作者: B. Casu*;A. Naggi;G. Torri
• 通讯作者: G. Torri

Significance of heparanase in cancer and inflammation.

乙酰肝素酶在癌症和炎症中的意义。

• 发表时间: 2012-08
• 作者: Vlodavsky, Israel;Beckhove, Phillip;Lerner, Immanuel;Pisano, Claudio;Meirovitz, Amichai;Ilan, Neta;Elkin, Michael
• 通讯作者: Elkin, Michael

Conformational changes of 1-4-glucopyranosyl residues of a sulfated C-C linked hexasaccharide.

硫酸化 C-C 连接六糖的 1-4-吡喃葡萄糖基残基的构象变化。

• 发表时间: 2014-05-07
• 影响因子: 3.1
• 作者: Coletti, Alessia;Elli, Stefano;Macchi, Eleonora;Galzerano, Patrizia;Zamani, Leila;Guerrini, Marco;Torri, Giangiacomo;Vismara, Elena
• 通讯作者: Vismara, Elena