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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.

项目概述（见说明）：