A Scalable, Direct‐to‐Biology Platform for Accelerated Discovery of Cereblon‐Based Molecular Glue Degraders
Abstract
ABSTRACT Molecular glue degraders (MGDs) offer transformative potential for expanding the druggable proteome; however, their discovery is severely impeded by mechanistic complexities that hinder rational design and synthetic bottlenecks that restrict the scale and diversity of E3 ligase‐centric compound libraries. Here, we introduce a general framework that transforms MGD discovery from a serendipity‐driven endeavor into a systematic, scalable pipeline by integrating modular, in situ library assembly with direct‐to‐biology phenotypic screening. Powered by biocompatible primary amine‐based photoclick chemistry, this platform enables the efficient, purification‐free generation of over 1000 structurally diverse cereblon (CRBN)‐centric molecules within days directly in multi‐well plates, facilitating a seamless transition from chemical synthesis to biological evaluation. Applying this strategy, we rapidly identified novel CRBN‐based MGDs that potently and selectively degrade GSPT1 or CK1α, as well as a multi‐target degrader of GSPT1/2 and stearoyl‐CoA desaturase (SCD). Crucially, our integrated validation highlights targeted CK1α degradation as a promising therapeutic strategy for prostate cancer. By leveraging the abundance and structural diversity of primary amines, this scalable platform expands the accessible chemical space, circumventing the complexities of de novo rational design. Ultimately, this work provides a streamlined engine for harnessing diverse E3 ligases, accelerating the development of next‐generation MGDs to tackle intractable diseases.
Article Details
Authors (17)
Jia‐Yu Wang
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Guang‐Liang Yin
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Yijia Chi
Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Yuan‐Peng Feng
School of Chinese Materia Medica Nanjing University of Chinese Medicine Nanjing China
Chu‐Cheng Zhou
School of Chinese Materia Medica Nanjing University of Chinese Medicine Nanjing China
Hui‐Jun Nie
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Zhi‐Gao Zhang
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Shuting Meng
School of Pharmacy Henan University Zhengzhou China
Yang Chen
Zhi‐Peng Zhou
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Jia‐Yu Zhang
School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences Hangzhou China
An Xu
Ye‐Kai Xu
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Linhui Zhai
Translational Research Institute of Brain and Brain‐Like Intelligence School of Medicine Shanghai Fourth People's Hospital Tongji University Shanghai China
Minjia Tan
State Key Laboratory of Drug Research
Dongxin Zhao
Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China
Xiao‐Hua Chen
State Key Laboratory of Drug Research Chinese Academy of Sciences Shanghai Institute of Materia Medica Shanghai P. R. China