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.
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.
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