发现 PARP1 蛋白质 ADP-核糖基化分离抑制剂

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-10-30 DOI:10.1021/acsmedchemlett.4c0039510.1021/acsmedchemlett.4c00395

Elisa N. Stephens, Liang-Chieh Chen, Arshad J. Ansari, Kaiyu Shen, Lei Zhang, Steven G. Guillen, Clay C. C. Wang and Yong Zhang*,

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引用次数: 0

摘要

聚 ADP 核糖聚合酶（PARPs）能催化细胞 ADP 核糖基化，在人类健康中发挥着重要作用。PARP 抑制剂已成功应用于临床癌症治疗。然而，为了提高安全性，还需要特异的同工酶抑制剂。在这里，我们报告了意外发现的烟酰胺模拟物，它们能在微摩尔浓度下阻断非 PARP1 催化的 ADP-核糖基化。这些PARP1-sparing PARP抑制剂代表了ADP-核糖基化的第一类探针，揭示了PARPs的选择性抑制。

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Discovery of PARP1-Sparing Inhibitors for Protein ADP-Ribosylation

Poly-ADP-ribose polymerases (PARPs) that catalyze cellular ADP-ribosylation play important roles in human health. PARP inhibitors have found success in the clinic for cancer treatment. However, isoform-specific inhibitors are needed for improved safety. Here, we report the unexpected discovery of nicotinamide mimics that block non-PARP1-catalyzed ADP-ribosylation at micromolar concentrations. These PARP1-sparing PARP inhibitors represent first-in-class probes for ADP-ribosylation, shedding light on the selective inhibition of PARPs.

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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.