Synthesis and Evaluation of DIM-like Analogues Targeting PI3K/Akt Pathway

靶向 PI3K/Akt 通路的 DIM 类似物的合成和评价

基本信息

批准号：
8552026
负责人：
John S Cooperwood
金额：
$ 7.37万
依托单位：
FLORIDA AGRICULTURAL AND MECHANICAL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8552026
关键词：
1-Phosphatidylinositol 3-Kinase Acids Active Sites Affect African American Aromatase Inhibitors Benzofurans Biological Factors Breast Cancer Cell Cancer Patient Cancer cell line Chemical Structure Chemopreventive Agent Community Services ERBB2 gene Epidermal Growth Factor Receptor Estradiol Estrogen Receptors Estrogen receptor negative Estrogens Evaluation Goals Growth Health Food Human Immunoblot Analysis Indole-3-Carbinol Inhibition of Apoptosis Instruction Mammary Neoplasms Marketing Methanol Molecular Models Pathway interactions Population Preventive Protein-Serine-Threonine Kinases Research Project Grants Research Training Selective Estrogen Receptor Modulators Signal Pathway Surveys Therapeutic Time United States Food and Drug Administration Woman analog anticancer research benzothiophene cancer therapy chemotherapeutic agent computer studies cruciferous vegetable dietary supplements experience malignant breast neoplasm molecular modeling mortality progesterone receptor negative triple-negative invasive breast carcinoma tumor

项目摘要

PROJECT SUMMARY (See instructions): Research Project 3 - Synthesis and Evaluation of DIM-like Analogues Targeting PI3K/Akt Pathway: John Cooperwood, Carl B. Goodman and Hernan A. Flores-Rozas: Recent surveys have shown that African-American women develop highly aggressive breast tumors and experience about three-time higher mortality rates in comparison with other populations. Most African-American women have estrogen receptor negative (ER-), progesterone receptor negative (PR-) and human epidermal growth factor receptor-2 negative (HER-2-) tumors. Current Food and Drug Administration (FDA)-approved breast cancer therapies are geared toward the treatment of estrogen positive (ER+) breast tumors, which include Selective Estrogen Receptor Modulators (SERMs) and Aromatase inhibitors. Both SERMs and aromatase inhibitors serve to alleviate the estrogen effect upon the progression of ER+ breast cancers. Nevertheless, there is a lack of treatment for triple negative (ER-, PR- and HER-2- ) breast cancer which overwhelmingly affects African-American women. This proposal's emphasis is directed toward a natural occurring potential chemopreventive and/or chemotherapeutic agent, indole-3-carbinol, which has been found to display both preventive and therapeutic anti-breast cancer activities in various studies, lndole-3-carbinol is a product found in cruciferous vegetables, and it is being marketed in health food stores as a dietary supplement. The key metabolite of lndole-3-carbinol is its acid form which is converted to other intermediates, such as 3, 3'dlindolylmethane (DIM). Our hypothesis is that DIM induces apoptosis by the inhibition of phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (Akt,) signaling pathway by antagonism at active site which is involved the stimulation of triple negative breast cancer growth by estradiol. This hypothesis has been substantiated by preliminary molecular modeling studies which indicate that there is similarity between the chemical structures of DIM analogues and estradiol. We will validate our hypothesis by the following specific aims: 1. Synthesis of hydroxlyated, benzofuran and benzothiophene DIM analogues. 2. Anti-proliferation Studies using MDA-MB-231, MDA-MB-435 and MDA-MB-435 estrogen receptor triple negative breast cancer cell lines, and Inhibition of Akt signal pathway using Immunoblot analysis, 3. Computational Studies for optimization of breast cancer growth inhibitory activity.

项目摘要（请参阅说明）：研究项目3-针对PI3K/AKT途径的昏暗类似物的综合和评估： John Cooperwood，Carl B. Goodman和Hernan A. Flores-Rozas：最近的调查表明，与其他人群相比，非洲裔美国妇女患有高度侵略性的乳腺肿瘤，并且经历了三次较高的死亡率。大多数非裔美国妇女的雌激素受体阴性（ER-），孕酮受体阴性（PR-）和人表皮生长因子受体-2阴性（HER-2-）肿瘤。目前的食品药品监督管理局（FDA） - 批准的乳腺癌疗法旨在治疗雌激素阳性（ER+）乳腺肿瘤，其中包括选择性雌激素受体调节剂（Serm）和芳香酶抑制剂。 Serm和芳香酶抑制剂均可减轻雌激素对ER+乳腺癌进展的影响。然而，缺乏三重阴性（ER-，PR-和HER-2-）乳腺癌的治疗方法，这对非裔美国妇女产生了压倒性的影响。该提议的重点是针对自然发生的潜在化学预防和/或化学治疗剂吲哚-3-甲醇在各种研究中，LNDOLE-3-甲醇是在十字花科蔬菜中发现的一种产品，在各种研究中，预防性和治疗性抗胸腺癌活性是一种膳食补充剂，它在健康食品商店中被销售。 LNDOLE-3-甲醇的关键代谢产物是其酸性形式，它转化为其他中间体，例如3，3'd'dlindolylylmethane（DIM）。我们的假设是，通过抑制雌激素的拮抗位点，通过拮抗位点抑制磷脂酰肌醇3-激酶（PI3K）/丝氨酸 - 硫代硫代激酶（Akt，）信号传导途径，从而诱导凋亡。初步分子建模研究证实了这一假设，该研究表明，昏暗类似物和雌二醇的化学结构之间存在相似性。我们将通过以下特定目的来验证我们的假设：1。羟化，苯并呋喃和苯甲噻吩二聚体类似物的合成。 2。使用MDA-MB-231，MDA-MB-435和MDA-MB-435雌激素受体三分阴性乳腺癌细胞系以及使用免疫印记分析抑制AKT信号途径的抗增殖研究，3。用于优化乳腺癌生长抑制活性的计算研究。