发现和优化作为芳基烃受体拮抗剂的吡唑并[1,5-a]嘧啶。

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Raitis Bobrovs, Svetlana Terentjeva, Ninni Elise Olafsen, Zilvinas Dambrauskas, Antanas Gulbinas, Toivo Maimets, Indrek Teino, Aigars Jirgensons, Jason Matthews and Kristaps Jaudzems
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引用次数: 0

摘要

芳基烃受体(AHR)是一种依赖配体的多功能转录因子,参与了从新陈代谢适应到免疫系统调节等多种生物过程。由于 AHR 在癌症免疫学中的关键作用,它已成为癌症治疗的一个有希望的靶点。在此,我们报告了新型 AHR 拮抗剂的发现和结构-活性关系研究。潜在的 AHR 拮抗剂是通过基于同源物模型的高通量虚拟筛选确定的,并在荧光素酶报告基因测定中进行了实验验证。对鉴定出的基于吡唑并[1,5-a]嘧啶的 AHR 拮抗剂 7(IC50 = 650 nM)进行了系统优化,以阐明其结构-活性关系,并达到低纳摩尔 AHR 拮抗效力(7a,IC50 = 31 nM)。总之,本文介绍的研究结果为 AHR 拮抗剂的开发提供了新的起点,并为 AHR 拮抗剂的结构-活性关系提供了深刻的信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Discovery and optimisation of pyrazolo[1,5-a]pyrimidines as aryl hydrocarbon receptor antagonists†

Discovery and optimisation of pyrazolo[1,5-a]pyrimidines as aryl hydrocarbon receptor antagonists†

Discovery and optimisation of pyrazolo[1,5-a]pyrimidines as aryl hydrocarbon receptor antagonists†

The aryl hydrocarbon receptor (AHR) is a versatile ligand-dependent transcription factor involved in diverse biological processes, from metabolic adaptations to immune system regulation. Recognising its pivotal role in cancer immunology, AHR has become a promising target for cancer therapy. Here we report the discovery and structure–activity relationship studies of novel AHR antagonists. The potential AHR antagonists were identified via homology model-based high-throughput virtual screening and were experimentally verified in a luciferase reporter gene assay. The identified pyrazolo[1,5-a]pyrimidine-based AHR antagonist 7 (IC50 = 650 nM) was systematically optimised to elucidate structure–activity relationships and reach low nanomolar AHR antagonistic potency (7a, IC50 = 31 nM). Overall, the findings presented here provide new starting points for AHR antagonist development and offer insightful information on AHR antagonist structure–activity relationships.

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来源期刊
CiteScore
5.80
自引率
2.40%
发文量
129
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