Nitric Oxide Chimera Drugs for Colon Cancer Chemoprevention

描述(由申请人提供)： 在美国，结直肠癌(CRC)是主要的死亡原因：结直肠癌的化学预防是一个重要的治疗目标，也是一个未得到满足的需求。抗炎药(NSAIDs，COX-2s)在临床前研究和临床试验中显示出良好的前景，但会带来严重的胃肠道(GI)或心血管副作用。NO供体非甾体抗炎药(NSAIDs)是一种脂肪族硝酸盐，是利用一氧化氮(NO)的生物活性来对抗NSAIDs的胃肠道副作用而设计的，已经在临床上得到了证实。根据NO-ASA的数据和我们关于GT 094的初步数据，没有嵌合体(含有一个或多个额外药效团的脂肪族硝酸盐)，我们认为没有嵌合体是结直肠癌化学预防的候选药物，GT-094代表先导化合物。这项建议的目标是建立非嵌合体药物，特别是含有非甾体抗炎药的药效团的构效关系(SAR)，研究(I)抗炎(Ii)抗增殖(Iii)阶段2(细胞保护)酶诱导和(Iv)凋亡活性，以使结构与活性相关联。其目的是设计和优化用于结直肠癌化学预防的候选药物或联合疗法。异常隐窝病灶(ACF)被认为是人类结肠腺瘤和癌症的早期先兆；在动物模型中，ACF数量与肿瘤发生有很好的相关性。这项建议的目的是在动物模型中测量与结直肠癌发生相关的ACF损伤和炎症和增殖的生物标记物，并在细胞培养中与这些标记物相关联。成功将源于我们在NO药物化学和ACF病理生理学方面的独特专业知识组合。具体目的：1.利用大鼠结直肠癌AOM模型，在体内评价非嵌合体先导剂GT 094的药效、疗效和作用机制，进而评价优化的非嵌合体候选药物和联合治疗方案。2.设计和合成非嵌合体、组成结构元件和控制化合物，以优化结构，从而达到预防结直肠癌的目的。3.研究这些化合物在结肠细胞培养中的作用，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。完成这些目标将产生用于结直肠癌化学预防的新候选药物，并提高对结直肠癌化学预防途径的了解。公共卫生相关性：开发非嵌合体药物，特别是含有二硫化物的非甾体抗炎药的构效关系，了解其对抗炎和抗增殖活性的贡献，从而设计用于结直肠癌化学预防的优化候选药物。异常隐窝病灶(ACF)被认为是人类结肠腺瘤和癌症的早期先兆；在动物模型中，ACF数量与肿瘤发生有很好的相关性。

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.