Indole-3-carbinol derivatives with enhanced chemopreventive activities

描述（由申请人提供）： 在肿瘤发生过程中，癌细胞通过组成性上调与细胞增殖和存活相关的多个信号通路来克服基因组不稳定性。这种肿瘤异质性给癌症患者的临床管理以及有效预防和治疗策略的开发带来了挑战。解决这个问题的合理策略是用强效多效药物同时靶向不同的分子异常，以改善临床结果。这一基本原理构成了我们对吲哚-3-甲醇结构进行优化的分子基础，以开发具有多效性机制模式的有效抗肿瘤药物，最终产生了酸稳定衍生物 OSU-A9。 OSU-A9 的抗肿瘤活性高出 100 倍，并且在靶向癌细胞中的多个信号传导靶点的效果方面具有惊人的相似性。尽管机制模式复杂，但非恶性细胞对 OSU-A9 的抗增殖作用不太敏感。因此，该项目检验了我们的假设，即使用针对与肿瘤发生和肿瘤进展相关的多种信号通路的多效性药物代表了癌症预防的有效策略，其目的是双重的。目标 1 是继续 OSU-A9 的结构修饰和最佳衍生物的机理验证。将生成两个系列的衍生物，其中OSU-A9的吲哚环被具有不同立体电子性质的取代基取代。我们预计该目标将产生 3 种抗肿瘤活性低至亚 5M 效力的最佳衍生物，用于机制验证和体内测试。目标 2 是评估最佳 OSU-A9 衍生物在小鼠前列腺转基因腺癌​​ (TRAMP) 模型中阻断前列腺肿瘤发生的体内功效。我们假设最佳的 OSU-A9 衍生物可以在临床可达到的浓度下阻断体内前列腺肿瘤的发生。该目标由三部分组成。首先是确定裸鼠体内 OSU-A9 及其最佳衍生物的口服最大耐受剂量。其次是确定体内功效并确定这些药物在 PC-3 异种移植肿瘤模型中的潜在毒性。第三是评估它们在 TRAMP 模型中的化学预防活性。我们期望这些最佳衍生物相对于吲哚-3-甲醇和其他植物化学物质在培育潜在的成功策略来阻止或延迟前列腺肿瘤发生和/或肿瘤进展方面将提供相当大的优势。公共卫生相关性：项目叙述 在男性中，前列腺癌是最常诊断出的癌症，也是癌症死亡的第二大原因。我们的总体研究目标是开发针对前列腺癌细胞中特定分子和细胞缺陷的新型药物，这些缺陷使得该疾病的临床管理和预防策略的开发变得非常具有挑战性。我们预计该项目最终将产生能够阻止或延缓前列腺癌发生和/或进展的新药。

DESCRIPTION (provided by applicant): During the course of tumorigenesis, cancer cells overcome genomic instability by constitutively up-regulating multiple signaling pathways pertinent to cell proliferation and survival. This tumor heterogeneity poses challenges to the clinical management of cancer patients and to the development of effective preventive and therapeutic strategies. A rational strategy to address this issue is the concomitant targeting of different molecular abnormalities with a potent pleiotropic agent to improve clinical outcomes. This rationale constitutes the molecular basis for our structural optimization of indole-3-carbinol to develop potent antitumor agents with pleiotropic modes of mechanism, which has culminated in the generation of an acid-stable derivative, OSU-A9. OSU-A9 exhibits a 100-fold higher antitumor activity and striking similarities in its effects on targeting multiple signaling targets in cancer cells. Despite this complex mode of mechanisms, nonmalignant cells were less susceptible to the antiproliferative effect of OSU-A9. This project thus tests our hypothesis that use of a pleiotropic agent that targets multiple signaling pathways associated with oncogenesis and tumor progression represents an effective strategy for cancer prevention, of which the aim is twofold. Aim 1 is to continue the structural modification of OSU-A9 and mechanistic validation of optimal derivatives. Two series of derivatives will be generated, in which the indole ring of OSU-A9 is substituted with substituents with different stereoelectronic properties. We expect that this Aim will generate 3 optimal derivatives with low to sub-5M potency in antitumor activity for mechanistic validation and in vivo testing. Aim 2 is to assess the in vivo efficacy of the optimal OSU-A9 derivatives on blocking prostate tumorigenesis in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. We hypothesize that the optimal OSU-A9 derivative can block prostate tumorigenesis in vivo at clinically attainable concentrations. This Aim consists of three parts. First is to determine the oral maximum tolerated doses of OSU-A9 and its optimal derivatives in nude mice. Second is to determine the in vivo efficacies and to identify potential toxicities of these agents in the PC- 3 xenograft tumor model. Third is to evaluate their chemopreventive activities in the TRAMP model. We expect that these optimal derivatives will provide considerable advantages relative to indole-3-carbinol and other phytochemicals in fostering potentially successful strategies to block or delay prostate tumorigenesis and/or tumor progression. PUBLIC HEALTH RELEVANCE: Project narrative In men, prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death. Our overall research goal is to develop novel agents that target the specific molecular and cellular defects in prostate cancer cells that make the clinical management and development of preventive strategies for this disease so challenging. We expect that this project will ultimately yield new drugs that will block or delay the development and/or the progression of prostate cancer.