推进TET抑制剂的发展：从结构洞察到生物学评价

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-04-08 DOI:10.1021/acsmedchemlett.5c0004210.1021/acsmedchemlett.5c00042

Suzanne Willems, Lejla Maksumic, Janina Niggenaber, Tzu-Chen Lin, Tom Schulz, Jörn Weisner, Sonja Sievers, Matthias P. Müller, Daniel Summerer* and Daniel Rauh*,

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引用次数: 0

摘要

10 - 11易位（TET）甲基胞嘧啶双加氧酶是消除DNA甲基化的表观遗传调控机制的一部分。异常TET活性经常在造血恶性肿瘤中发现，其中TET2功能的丧失导致DNA超甲基化。全面了解tet的生物学作用对于阐明疾病发病机制和确定新的治疗策略至关重要。我们提出了一个整合蛋白质x射线晶体学，分子建模和药效团分析的强大管道，以推进当前TET抑制剂的开发。此外，我们还合成并评价了一系列8-羟基喹啉（8-HQ）衍生物，证明了它们作为进一步探索TET功能的化学工具的潜力。这些发现为以tet为中心的治疗方法奠定了基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Advancing TET Inhibitor Development: From Structural Insights to Biological Evaluation

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Advancing TET Inhibitor Development: From Structural Insights to Biological Evaluation

Ten-eleven translocation (TET) methylcytosine dioxygenases are part of the epigenetic regulatory machinery that erases DNA methylation. Aberrant TET activities are frequently found in hematopoietic malignancies, where loss of TET2 function leads to DNA hypermethylation. A comprehensive understanding of the biological role of TETs is essential to elucidate disease pathogenesis and identify novel therapeutic strategies. We present a robust pipeline integrating protein X-ray crystallography, molecular modeling, and pharmacophore analysis to advance the current TET inhibitor development. In addition, we have synthesized and evaluated a series of 8-hydroxyquinoline (8-HQ) derivatives, demonstrating their potential as chemical tools to explore TET function further. These findings lay the groundwork for a TET-centered therapeutic approach.

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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.