Nitric Oxide Chimera Drugs for Colon Cancer Chemoprevention

用于结肠癌化学预防的一氧化氮嵌合药物

• 批准号: 7774413
• 负责人: Gregory R. J Thatcher
• 金额: $ 31.77万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7774413
• 关键词: Aberrant crypt foci; Accounting; Adverse effects; Adverse event; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Apoptotic; Aspirin; Attenuated; Azoxymethane; Biological; Biological Assay; Biological Markers; Cancer cell line; Carcinogens; Cardiovascular system; Cause of Death; Cell Culture Techniques; Cell Line; Chemoprevention; Chemopreventive Agent; Chimera organism; Clinic; Clinical; Clinical Trials; Colon; Colon Carcinoma; Colonic Adenoma; Colorectal Cancer; Combined Modality Therapy; DNA Damage; Data; Databases; Development; Disulfides; Dose; Elements; Endoscopy; Enzyme Induction; Enzymes; Event; Explosion; Functional disorder; Genus Cola; Goals; Human; In Vitro; Incidence; Individual; Indomethacin; Induction of Apoptosis; Inflammation; Inflammatory Response; Intervention; Isosorbide Dinitrate; Kupffer Cells; Lead; Length; Lesion; Light; Link; Malignant Neoplasms; Measures; Metabolic; Modeling; Mutation; New Agents; Nitrates; Nitric Oxide; Nitric Oxide Donors; Non-Steroidal Anti-Inflammatory Agents; PTGS2 gene; Pathology; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Pilot Projects; Polyps; Pre-Clinical Model; Prevention; Principal Investigator; Proliferation Marker; Property; Prostaglandins; Proteins; Rattus; Reducing Agents; Reporting; Risk; Rodent; Screening procedure; Signal Pathway; Staging; Stem cells; Structure; Structure-Activity Relationship; Testing; Therapeutic; Time; Time Study; Tissues; adenoma; arm; base; cancer chemoprevention; cancer risk; chimera drug; design; drug candidate; gastrointestinal; improved; in vitro activity; in vivo; inhibitor/antagonist; man; metabolic abnormality assessment; mimetics; novel; pharmacophore; pre-clinical research; programs; public health relevance; small molecule; success; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a leading cause of death in the US: chemoprevention of CRC represents an important therapeutic target and an unmet need. Anti-inflammatory agents (NSAIDs, COX-2s) have shown promise in preclinical research and clinical trials, but carry the burden of severe gastrointestinal (GI) or cardiovascular side effects. NO-donor NSAIDs, which are aliphatic nitrates, were designed to utilize the biological activity of nitric oxide (NO) to counteract the GI side effects of NSAIDs, which been borne out in the clinic. On the basis of data on NO-ASA and our preliminary data on GT 094, NO chimera (aliphatic nitrates containing one or more additional pharmacophores) we propose that NO chimeras are drug candidates for CRC chemoprevention and GT-094 represents a lead compound. It is the goal of this proposal to develop structure activity relationships (SAR) for NO chimera drugs, in particular containing NSAID containing pharmacophores, studying (i) anti- inflammatory (ii) anti-proliferative (iii) phase 2 (cytoprotective) enzyme inductiion and (iv) apoptotic activity activity, to correlate structurewith activity. The objective is to design and optimize a drug candidate or combination therapy for CRC chemoprevention. Aberrant crypt foci (ACF) are seen as an early precursor stage to colon adenomas and cancer in man; and in animal models a good correlation between ACF number and tumorigenesis has been reported. It is an objective of this proposal to measure ACF lesions and biomarkers of inflammation and proliferation that correlate with CRC tumorigenesis in animal models, and to correlate with such markers in cell culture. Success will result from our unique combination of expertise in NO-based medicinal chemistry and ACF pathophysiology. Specific aims: 1. To use the rat AOM model of CRC to assess in vivo the potency, efficacy and mechanism of the lead NO chimera, GT 094, and subsequently, to assess optimized NO chimera drug candidates and combination therapies. 2. To design and synthesize NO chimeras, component structural elements, and control compounds to optimize structure towards CRC chemoprevention. 3. To study these compounds in colon cell culture, to derive SAR correlations and to establish correlations with in vivo activity, to aid in design and optimazation of drug candidates. Completion of these aims will yield new drug candidates for CRC chemoprevention and improved understanding of chemopreventive pathways in CRC. PUBLIC HEALTH RELEVANCE: To develop structure activity relationships for NO chimera drugs, in particular NSAID containing disulfides, to understand the contributions to anti-inflammatory and anti-proliferative activity, and thus to design optimized drug candidates for CRC chemoprevention. Aberrant crypt foci (ACF) are seen as an early precursor stage to colon adenomas and cancer in man; and in animal models a good correlation between ACF number and tumorigenesis has been reported.

描述（由申请人提供）： 结直肠癌 (CRC) 是美国的一个主要原因：结直肠癌的化学预防是一个重要的治疗目标和未满足的需求。抗炎药（NSAID、COX-2）在临床前研究和临床试验中显示出前景，但会带来严重的胃肠道 (GI) 或心血管副作用。 NO 供体 NSAID 是脂肪族硝酸盐，旨在利用一氧化氮 (NO) 的生物活性来抵消 NSAID 的胃肠道副作用，这一点已在临床中得到证实。根据 NO-ASA 的数据和我们对 GT 094、NO 嵌合体（含有一种或多种其他药效基团的脂肪族硝酸盐）的初步数据，我们建议 NO 嵌合体是 CRC 化学预防的候选药物，而 GT-094 代表一种先导化合物。本提案的目标是开发 NO 嵌合药物的结构活性关系 (SAR)，特别是含有 NSAID 的药效团，研究 (i) 抗炎 (ii) 抗增殖 (iii) 第 2 相（细胞保护）酶诱导和 (iv) 细胞凋亡活性，以将结构与活性关联起来。目的是设计和优化用于 CRC 化学预防的候选药物或联合疗法。异常隐窝病灶 (ACF) 被视为人类结肠腺瘤和癌症的早期前兆；在动物模型中，ACF 数量与肿瘤发生之间存在良好的相关性。该提案的目的是在动物模型中测量与 CRC 肿瘤发生相关的 ACF 病变以及炎症和增殖的生物标志物，并与细胞培养中的此类标志物相关联。成功将源自我们在基于 NO 的药物化学和 ACF 病理生理学方面的专业知识的独特结合。具体目标： 1. 使用CRC大鼠AOM模型在体内评估先导NO嵌合体GT 094的效力、功效和机制，并随后评估优化的NO嵌合体候选药物和联合疗法。 2. 设计和合成NO嵌合体、组分结构元件和控制化合物，以优化结构以实现CRC化学预防。 3. 在结肠细胞培养物中研究这些化合物，得出 SAR 相关性并建立与体内活性的相关性，以帮助设计和优化候选药物。这些目标的完成将产生用于结直肠癌化学预防的新候选药物，并加深对结直肠癌化学预防途径的了解。公共卫生相关性：开发 NO 嵌合药物（特别是含有二硫化物的 NSAID）的结构活性关系，以了解其抗炎和抗增殖活性的贡献，从而设计用于 CRC 化学预防的优化候选药物。异常隐窝病灶 (ACF) 被视为人类结肠腺瘤和癌症的早期前兆；在动物模型中，ACF 数量与肿瘤发生之间存在良好的相关性。