Nitric Oxide Chimera Drugs for Colon Cancer Chemoprevention

描述（由申请人提供）： 结直肠癌（CRC）是美国的主要死亡原因：CRC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，考克斯-2）已在临床前研究和临床试验中显示出前景，但具有严重的胃肠道（GI）或心血管副作用的负担。一氧化氮供体非甾体抗炎药是一种脂肪族硝酸盐，旨在利用一氧化氮（NO）的生物活性来抵消非甾体抗炎药的胃肠道副作用，这在临床上得到了证实。基于关于NO-ASA的数据和我们关于GT 094、NO嵌合体（含有一个或多个额外药效团的脂肪族硝酸酯）的初步数据，我们提出NO嵌合体是用于CRC化学预防的候选药物，GT-094代表先导化合物。本提案的目标是开发NO嵌合体药物的结构活性关系（SAR），特别是含有含药效团的NSAID，研究（i）抗炎（ii）抗增殖（iii）2相（细胞保护）酶诱导和（iv）凋亡活性，以将结构与活性相关联。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阶段;在动物模型中，ACF数量与肿瘤发生之间存在良好的相关性。本建议的目的是测量动物模型中与CRC肿瘤发生相关的ACF病变和炎症和增殖的生物标志物，并与细胞培养物中的此类标志物相关。成功将来自于我们在NO为基础的药物化学和ACF病理生理学方面的独特专业知识。具体目标：1.使用CRC的大鼠AOM模型来评估体内先导NO嵌合体GT 094的效力、功效和机制，并且随后评估优化的NO嵌合体候选药物和组合疗法。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，实现CRC化学预防。3.在结肠细胞培养中研究这些化合物，推导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新的候选药物用于CRC化学预防，并提高对CRC化学预防途径的理解。公共卫生相关性：开发NO嵌合体药物，特别是含有二硫化物的NSAID的结构活性关系，以了解其对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阶段;在动物模型中，ACF数量与肿瘤发生之间存在良好的相关性。

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.