AHR-Protac, a novel aryl hydrocarbon receptor antagonist

描述(由申请人提供)：本提案的广泛、长期目标是使用在此开发的一类新型芳烃受体(AHR)拮抗剂AHR-Protaks，作为1)研究工具来描述环境因素激活AHR途径导致人类癌症发生的机制，并确定AHR在其他疾病过程中的作用以及2)治疗癌症、糖尿病和心血管疾病的治疗剂。环境因素，如苯并[a]芘和2，3，7，8-四氯二苯并-对二恶英(TCDD)的暴露被认为在人类癌症的发展中起着重要作用。虽然已知这些药物通过激活AHR发挥其许多致癌作用，但AHR引发关键事件的机制尚不清楚。此外，目前尚未确定以AHR为靶点是否为有效的化学预防方法。最后，新出现的证据表明，AHR不仅在癌症中发挥作用，而且在糖尿病和心血管疾病中也发挥作用。当前建议的近期目标是优化和表征新型AHR拮抗剂，其中一些已经在我们的实验室开发，作为适当的AHR拮抗剂。具体目标：(1)最佳AHR蛋白的合成。(2)确定最适AHR蛋白分子(S)对培养细胞AHR信号的高效抑制作用。(3)确定最佳AHR蛋白(S)是否抑制TCDD改变细胞周期、细胞凋亡和衰老的能力。(4)确定最佳AHR蛋白(S)是否具有高度特异性地改变AHR通路。本文提出的工作将开发一种新的研究工具，可用于确定环境致癌物对AHR的不适当激活如何导致人类癌症，并了解AHR在正常生物过程中的作用。此外，这项工作将为开发针对AHR的药物奠定基础，可能不仅作为预防癌症的药物在临床上有用，而且在治疗糖尿病和心血管疾病方面也可能有效。

DESCRIPTION (provided by applicant): The broad, long term goals of this proposal are to use a novel class of antagonists of the aryl hydrocarbon receptor (AHR), AHR-Protacs, developed herein as 1) a research tool to delineate the mechanisms by which activation of the AHR pathway by environmental agents leads to carcinogenesis in the human population and identify roles of the AHR in other disease processes and 2) a therapeutic agent to treat cancers, diabetes and cardiovascular diseases. Exposures to environmental factors, such as benzo[a]pyrene and 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) are thought to play important roles in the development of human cancers. While these agents are known to exert many of their carcinogenic actions via activation of the AHR, the mechanisms by which the AHR elicits the key events are unknown. Further, it has not yet been established whether targeting the AHR would be an effective chemopreventive approach. Finally, emerging evidence implicates a role for the AHR in not only cancer, but also diabetes and cardiovascular diseases. The immediate goals of the current proposal are to optimize and characterize novel AHR antagonists, some of which have already been developed in our laboratories, as appropriate AHR antagonists. Specific Aims: (1) Synthesis of optimum AHR Protacs. (2) Determine that the optimum AHR Protac molecule(s) inhibits AHR signaling in cultured cells with high efficacy. (3) Determine whether the optimum AHR Protac(s) inhibits the ability of TCDD to alter cell cycle, apoptosis and senescence. (4) Determine whether the optimum AHR Protac(s) alters the AHR pathway with high specificity. The work proposed herein will develop a novel research tool that can be used to identify how inappropriate activation of the AHR by environmental carcinogens leads to human cancers and to understand the role of the AHR in normal biological processes. In addition, this work will set the stage for the development of drugs that target the AHR and may be clinically useful not only as agents that may prevent cancers, but may also be effective in the treatment of diabetes and cardiovascular diseases.