Rational Design of Molecular Glues: Breakthroughs and Perspectives

doi:10.26434/chemrxiv-2023-50fwj-v2

	Rational Design of Molecular Glues: Breakthroughs and Perspectives
	An, Juzeng1 ; Zhang, Xiaojun 2
	2024-01-02
状态	已发表
摘要	CRBN is a substrate receptor for the Cullin Ring E3 ubiquitin ligase 4 (CRL4) complex. It has been observed that CRBN can be exploited by small molecules to facilitate the recruitment and ubiquitination of non-natural CRL4 substrates, resulting in the degradation of neo-substrate through the ubiquitin-proteasome system. This phenomenon, known as molecular glue induced protein degradation, has emerged as an innovative therapeutic approach in contrast to traditional small-molecule drugs. One key advantage of molecular glues, in comparison to conventional small-molecule drugs adhering to Lipinski's Rule of Five, is their ability to operate without the necessity for specific binding pockets on target proteins. This unique characteristic empowers molecular glues to interact with conventionally intractable protein targets, such as transcription factors and scaffold proteins. The ability to induce the degradation of these previously elusive targets by hijacking the ubiquitin-proteasome system presents a promising avenue for the treatment of recalcitrant diseases. Nevertheless, the rational design of molecular glues remains a formidable challenge due to the limited understanding of their mechanisms and actions. This review offers an overview of recent advances and breakthroughs in the field of CRBN-based molecular glues, while also exploring the prospects for a systematic approach to designing these compounds.
关键词	CRBN Molecular Glue Rational Design Degradation Ubiquitination
语种	英语
DOI	10.26434/chemrxiv-2023-50fwj-v2
相关网址	查看原文
出处	chemRxiv
收录类别	PPRN.PPRN
WOS记录号	PPRN:86899518
WOS类目	Chemistry, Multidisciplinary
文献类型	预印本
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/349901
专题	生命科学与技术学院生命科学与技术学院_PI研究组_仓勇组
通讯作者	Zhang, Xiaojun
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 2.Shanghai Degron Therapeut, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	An, Juzeng,Zhang, Xiaojun. Rational Design of Molecular Glues: Breakthroughs and Perspectives. 2024.