LIN28-Targeting Chromenopyrazoles and Tetrahydroquinolines Induced Cellular Morphological Changes and Showed High Biosimilarity with BRD PROTACs.

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL ChemMedChem Pub Date : 2024-10-01 DOI:10.1002/cmdc.202400547

Mao Jiang, Nicole Giannino, Georg L Goebel, Sonja Sievers, Peng Wu

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Abstract

The probing of small molecules with heterocyclic scaffolds covering unexplored chemical space and the evaluation of their biological relevance are essential parts of forward chemical genetics approaches and for the development of potential small-molecule therapeutics. In this study, we profiled sets of chromenopyrazoles (CMPs) and tetrahydroquinolines (THQs), originally developed to target the protein-RNA interaction of LIN28-let-7, in a cell painting assay (CPA) measuring cellular morphological changes. Selected LIN28-inactive CMPs and THQs induced cellular morphological changes to different extents. The most CPA-active CMPs 2 and 3 exhibited high bio-similarity with the LCH and BET clusters, while the most CPA-active THQs 13 and 20 indicated a mechanism of action beyond the currently established biosimilarity clusters. Overall, this work demonstrated that CPA is useful in revealing "hidden" biological targets and mechanisms of action for biologically inactive small molecules, which are CMPs and THQs targeting the RNA-binding protein LIN28 in this case, evaluated in target-based strategies. When compared with annotated reference compounds, CMP 3 exhibited a high biosimilarity with the dual BRD7/9 degrading PROTAC VZ185, suggesting that CPA could potentially function as a new phenotypic approach to identify degrader molecules.

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LIN28靶向铬吡唑和四氢喹啉能诱导细胞形态变化，并与BRD PROTACs表现出高度生物相似性。

利用覆盖未开发化学空间的杂环支架探测小分子并评估其生物学相关性，是前瞻性化学遗传学方法和开发潜在小分子疗法的重要组成部分。在本研究中，我们在测量细胞形态变化的细胞涂色试验（CPA）中分析了几组色并吡唑（CMPs）和四氢喹啉（THQs），它们最初是针对 LIN28-let-7 的蛋白质-RNA 相互作用而开发的。选定的 LIN28 活性 CMP 和 THQs 在不同程度上诱导细胞形态发生变化。CPA 活性最强的 CMPs 2 和 3 与 LCH 和 BET 簇表现出高度的生物相似性，而 CPA 活性最强的 THQs 13 和 20 则表明其作用机制超出了目前已确立的生物相似性簇。总之，这项工作表明，CPA 有助于揭示无生物活性小分子的 "隐藏 "生物靶点和作用机制，本例中的小分子是以 RNA 结合蛋白 LIN28 为靶点的 CMP 和 THQ。与已注释的参考化合物相比，CMP 3 与 BRD7/9 双降解 PROTAC VZ185 具有很高的生物相似性，这表明 CPA 有可能作为一种新的表型方法来鉴定降解分子。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.