Studies of Structure–Activity Relationship of 2-(Pyrrolidin-1ylmethyl)-1H-pyrrole-Based ST2 Inhibitors and Their Inhibition of Mast Cells Activation

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-10-18 DOI:10.1021/acsmedchemlett.4c0045910.1021/acsmedchemlett.4c00459

Xinrui Yuan, Jason C. Rech, Andhavaram Ramaraju, Amol D. Patil, Krishani Rajanayake, Hebao Yuan, Mona Kazemi Sabzvar, Mousumi Mandal, Eun Bee Cho, Bo Wen, Jianxiong Jiang, M. Dennis Leo, Udai P. Singh, Duxin Sun and Chao-Yie Yang*,

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Abstract

ST2 belongs to the interleukin 1 receptor family and is expressed in immune cells including certain CD4⁺ T cells and mast cells. Binding of ST2 with interleukin 33 (IL-33) induces downstream signaling that activates NF-κB pathway. Although the ST2/IL-33 axis exerts immune tolerance via expansion of regulator T cells, the same axis also activates a subset of immune cells to produce proinflammatory cytokines in host defense or in tissue repair. Here, we reported the development of ST2 inhibitors with improved inhibitory activities against ST2 and metabolic stability based on a previous lead, iST2-14e. Using the human mast cell line (LAD2), we showed that ST2 inhibitors mitigated ST2 upregulation and reduced IL-1β released through degranulation, demonstrating that small-molecule ST2 inhibitors effectively attenuated the ST2/IL-33 signaling in human mast cells. Further optimization of the compounds may lay the foundation for developing ST2 inhibitors for the treatment of mast cells mediated diseases.

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基于 2-(吡咯烷-1-基甲基)-1H-吡咯的 ST2 抑制剂的结构-活性关系及其对肥大细胞活化的抑制作用研究

ST2 属于白介素 1 受体家族，在包括某些 CD4+ T 细胞和肥大细胞在内的免疫细胞中表达。ST2 与白介素 33（IL-33）结合会诱导激活 NF-κB 通路的下游信号。虽然 ST2/IL-33 轴通过调节性 T 细胞的扩增发挥免疫耐受作用，但同一轴还能激活免疫细胞亚群，在宿主防御或组织修复过程中产生促炎细胞因子。在此，我们报告了基于之前的先导物 iST2-14e 开发出的 ST2 抑制剂，它对 ST2 的抑制活性和代谢稳定性都有所提高。我们利用人体肥大细胞系（LAD2）研究发现，ST2 抑制剂能缓解 ST2 的上调并减少通过脱颗粒释放的 IL-1β，这表明小分子 ST2 抑制剂能有效减弱人肥大细胞中的 ST2/IL-33 信号传导。进一步优化这些化合物可为开发 ST2 抑制剂治疗肥大细胞介导的疾病奠定基础。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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