Nie, H.-J.; Wang, J.; Xu, H.; Zhou, Y.-J.; Yin, G.-L.; Xu, X.; Xu, G.; Chen, B.; Li, X.; Hu, X.; Zhou, Y.; Li, J.; Chen, X.-H.

Molecular glue degraders (MGDs) represent a transformative modality in drug discovery. Notably, the cereblon (CRBN)-MGD axis offers a broad opportunity for therapeutic intervention, serving as a strategic gateway to systematically target the historically undruggable proteome. However, the limited chemical diversity of CRBN-mediated MGDs has critically impeded the full exploration of the degradable proteome. Here, we introduce an innovative indazolone-based platform that transcends the canonical isoindolinone-glutarimide scaffolds, thereby significantly expanding the chemical space for CRBN modulation. Guided by mechanistic insights into CRBN-MGD complex conformational plasticity, our rational design yielded novel indazolone architectures demonstrating potent CRBN binding and unprecedented substrate programmability. This platform enabled fine-tuned control over neo-substrate recognition, leading to diverse degradation profiles from multi-target to exquisitely selective for critical proteins like IKZF1/3, ZFP91, LIMD1, CK1, and IKZF2. This work not only converts previously undruggable proteins into tractable therapeutic targets but also establishes novel strategies for challenging diseases, including hematological malignancies and solid tumors. Collectively, the indazolone-based architectures' remarkable tunability and favorable pharmacokinetic properties establish them as a powerful blueprint for next-generation MGD development, enabling systematic exploration of the vast CRBN-accessible target space. Furthermore, as superior CRBN ligands, they offer invaluable potential for both MGD and diverse PROTAC discovery to systematically address intractable diseases.