Sculpting Cell Fate: The Expanding Universe of Nondegradative Proximity-Inducing Tools

IF 3.4 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2026-02-12 DOI:10.1002/cmdc.202501088

Hangdi Xiao, Lan Wang, Mengxiao Chen, Tengfei Zhen, Yao Chen, Haopeng Sun

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Abstract

The paradigm of targeted therapy has been revolutionized by the development of proximity-inducing chimeras, particularly proteolysis-targeting chimeras (PROTACs), which offer a therapeutic strategy for previously “undruggable” targets. However, the degradation of certain essential proteins can lead to off-target toxicity, prompting the development of nondegradative proximity-inducing chimeras. This review categorizes current nondegradative chimeras into several functional classes, including targeted inhibition, targeted stabilization, post-translational modification (PTM), and cellular switches; elaborates on the mechanisms of action for each category; and introduces representative technologies, including molecular glues (MGs). Furthermore, the review highlights cutting-edge research and recent advancements in the field. Unlike previous reviews focusing primarily on degradative chimera technologies, this article systematically categorizes nondegradative modalities into inhibition, stabilization, PTM, and cellular switches, providing a unified mechanistic framework and highlighting emerging therapeutic applications beyond oncology.

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雕刻细胞的命运：不可降解的接近诱导工具的扩展宇宙

靶向治疗的范式已经被邻近诱导嵌合体的发展彻底改变，特别是蛋白水解靶向嵌合体（PROTACs），它为以前“不可药物”的靶标提供了治疗策略。然而，某些必需蛋白质的降解可能导致脱靶毒性，从而促进非降解邻近诱导嵌合体的发展。本文将目前的非降解嵌合体分为几个功能类别，包括靶向抑制、靶向稳定、翻译后修饰（PTM）和细胞开关；阐述了每一类的作用机制；介绍了分子胶（MGs）等具有代表性的技术。此外，该综述还重点介绍了该领域的前沿研究和最新进展。与以往主要关注降解嵌合体技术的综述不同，本文系统地将非降解模式分为抑制、稳定、PTM和细胞开关，提供了统一的机制框架，并强调了肿瘤以外的新兴治疗应用。

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.