化学诱导邻近时代的无靶点细胞筛选

Target agnostic cellular screening in the era of chemically induced proximity.

作者信息

Jin Meizhong

机构信息

Oncology R&D, AstraZeneca Waltham Massachusetts 02451 USA

出版信息

RSC Med Chem. 2025 Jul 21. doi: 10.1039/d5md00529a.

Abstract

We have enjoyed much success with target centric drug discovery as the leading approach in the past few decades. Target centric drug discovery starts with specific protein targets which are typically identified through diseases associated with human genetic changes such as mutations, or through genetic knock down or knock out methods, followed by additional functional validation. Despite successes, significant challenges remain: we often identify new protein targets that are deemed "undruggable"; also, for certain diseases, lack of clear understanding of underlying mechanisms prevents a target centric approach. Target agnostic cellular screening, as an alternative approach, has also been utilized in drug discovery to uncover unknown mechanisms behind a specific disease phenotype. While there have been noticeable successes, its application has been limited by the often perceived daunting process of mechanism-of-action deconvolution. Recently, a number of publications revealed examples of small molecules, identified from target agnostic cellular screenings, eliciting their function "chemically induced proximity". In many cases, the small molecules enable new protein-protein interactions that do not exist in the native cells, thus creating a "gain-of-function" effect that may not be recapitulated from knock down or knock out methods. In this perspective article, recent findings and their implications for drug discovery are discussed. Additionally, a general framework for target agnostic screening in the context of "chemically induced proximity" is proposed, aiming to maximize the efficiency of hit finding by balancing screening efforts with mechanism-of-action deconvolution, including key factors such as the nature of compounds for screening, assay format, and readout.

摘要

在过去几十年里,以靶点为中心的药物发现作为主要方法取得了很大成功。以靶点为中心的药物发现始于特定的蛋白质靶点,这些靶点通常通过与人类基因变化(如突变)相关的疾病来识别,或者通过基因敲低或敲除方法来识别,随后进行额外的功能验证。尽管取得了成功,但仍存在重大挑战:我们经常发现被认为“难以成药”的新蛋白质靶点;此外,对于某些疾病,由于对潜在机制缺乏清晰的了解,无法采用以靶点为中心的方法。作为一种替代方法,非靶点细胞筛选也已用于药物发现,以揭示特定疾病表型背后的未知机制。虽然已经取得了显著成功,但其应用受到了通常被认为艰巨的作用机制反卷积过程的限制。最近,一些出版物揭示了从非靶点细胞筛选中鉴定出的小分子通过“化学诱导邻近效应”发挥其功能的例子。在许多情况下,这些小分子能够实现天然细胞中不存在的新的蛋白质-蛋白质相互作用,从而产生一种“功能获得”效应,这种效应可能无法通过敲低或敲除方法重现。在这篇观点文章中,讨论了最近的发现及其对药物发现的影响。此外,还提出了一个在“化学诱导邻近效应”背景下进行非靶点筛选的通用框架,旨在通过平衡筛选工作与作用机制反卷积,包括筛选化合物的性质、检测形式和读数等关键因素,来最大化发现活性分子的效率。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索