Design and Assessment of First-Generation Heterobifunctional PPARα/STING Modulators

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-07-22 DOI:10.1021/acsmedchemlett.4c0015310.1021/acsmedchemlett.4c00153

Bo Hu, Yi Cui, Julia J. Lee, Jian-Xing Ma and Adam S. Duerfeldt*,

{"title":"Design and Assessment of First-Generation Heterobifunctional PPARα/STING Modulators","authors":"Bo Hu, Yi Cui, Julia J. Lee, Jian-Xing Ma and Adam S. Duerfeldt*, ","doi":"10.1021/acsmedchemlett.4c0015310.1021/acsmedchemlett.4c00153","DOIUrl":null,"url":null,"abstract":"Inflammatory retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD) are prominent causes of blindness in industrialized countries. The complexity of these diseases, involving diverse cell types and pathways that give rise to a multifactorial pathogenesis, complicates drug discovery. As such, therapies exhibiting polypharmacology are expected to improve outcomes through broader disease stage coverage and beneficial spatiotemporal effects. We report herein the first dual modulator of PPARα and STING, two targets tied to disparate pathologies in retinal diseases. Recognizing structural similarities between a reported STING inhibitor SN-013 and our previously described PPARα agonist A229, we designed BH400, which agonizes PPARα (EC50 = 1.2 μM) and inhibits STING (IC50 = 8.1 μM). BH400 demonstrates superior protection over single-target PPARα or STING modulation in microglial and photoreceptor cells. These findings provide compelling evidence for the potential benefit of polypharmacology in common retinal diseases through dual PPARα/STING modulation, motivating further studies.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 8","pages":"1279–1286 1279–1286"},"PeriodicalIF":4.0000,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00153","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Inflammatory retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD) are prominent causes of blindness in industrialized countries. The complexity of these diseases, involving diverse cell types and pathways that give rise to a multifactorial pathogenesis, complicates drug discovery. As such, therapies exhibiting polypharmacology are expected to improve outcomes through broader disease stage coverage and beneficial spatiotemporal effects. We report herein the first dual modulator of PPARα and STING, two targets tied to disparate pathologies in retinal diseases. Recognizing structural similarities between a reported STING inhibitor SN-013 and our previously described PPARα agonist A229, we designed BH400, which agonizes PPARα (EC₅₀ = 1.2 μM) and inhibits STING (IC₅₀ = 8.1 μM). BH400 demonstrates superior protection over single-target PPARα or STING modulation in microglial and photoreceptor cells. These findings provide compelling evidence for the potential benefit of polypharmacology in common retinal diseases through dual PPARα/STING modulation, motivating further studies.

Abstract Image

查看原文本刊更多论文

第一代异多功能 PPARα/STING 调节剂的设计与评估

在工业化国家，糖尿病视网膜病变（DR）和老年性黄斑变性（AMD）等炎症性视网膜疾病是致盲的主要原因。这些疾病十分复杂，涉及多种细胞类型和通路，导致多因素致病机理，从而使药物发现变得更加复杂。因此，多药理学疗法有望通过更广泛的疾病阶段覆盖范围和有益的时空效应来改善治疗效果。我们在此报告了首个 PPARα 和 STING 的双重调节剂，这两个靶点与视网膜疾病中不同的病理机制息息相关。认识到 STING 抑制剂 SN-013 与我们之前描述的 PPARα 激动剂 A229 在结构上的相似性，我们设计了 BH400，它能激动 PPARα（EC50 = 1.2 μM）并抑制 STING（IC50 = 8.1 μM）。BH400 对小胶质细胞和感光细胞的保护作用优于单靶点 PPARα 或 STING 调节。这些发现提供了令人信服的证据，证明通过 PPARα/STING 双重调节，多药理学对常见视网膜疾病具有潜在的益处，从而推动了进一步的研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

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.