AHR-Protac, a novel aryl hydrocarbon receptor antagonist

描述（申请人提供）：该提议的广泛的长期目标是使用一类新的芳烃受体（AHR）拮抗剂，AHR-Protacs，在此开发为1）一种研究工具，用于描述环境因子激活AHR途径导致人群致癌的机制，并确定AHR在其他疾病过程中的作用，以及2）用于治疗癌症、糖尿病和心血管疾病的治疗剂。苯并[a]芘和2，3，7，8-四氯二苯并-对-二恶英（TCDD）等环境因子的暴露被认为在人类癌症的发展中起重要作用。虽然已知这些物质通过激活AHR发挥其许多致癌作用，但AHR激发关键事件的机制尚不清楚。此外，尚未确定靶向AHR是否是有效的化学预防方法。最后，新的证据表明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。目前的建议的直接目标是优化和表征新的AHR拮抗剂，其中一些已经在我们的实验室中开发，作为适当的AHR拮抗剂。具体目的：（1）合成最佳的AHR蛋白。(2)确定最佳AHR Protac分子以高效抑制培养细胞中的AHR信号传导。(3)确定最佳AHR Protac是否抑制TCDD改变细胞周期、凋亡和衰老的能力。(4)确定最佳AHR Protac是否以高特异性改变AHR途径。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，这项工作将为开发靶向AHR的药物奠定基础，不仅可以作为预防癌症的药物，而且还可以有效治疗糖尿病和心血管疾病。

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.