Indazolone-Based Molecular Glue Degraders as a Tunable Platform for Reprogramming Cereblon Substrate Specificity

Molecular glue degraders (MGDs) represent a transformative modality in drug discovery, with the cereblon (CRBN) MGD axis offering a strategic gateway to systematically address the historically undruggable proteome. However, the limited chemical diversity of existing CRBN mediated MGDs has constrained the full exploration of the degradable landscape. Here, we introduce an innovative indazolone based platform that extends beyond canonical isoindolinone glutarimide scaffolds, significantly expanding the accessible chemical space for CRBN modulation. Guided by mechanistic insights into CRBN-MGD complex conformational plasticity, we rationally designed indazolone architectures as novel CRBN ligands, developing diverse MGDs with potent ligase binding and exceptional substrate programmability. This platform enables fine-tuned control over neo-substrate recognition, supporting diverse degradation profiles ranging from the broad targeting of critical proteins (IKZF1/3, ZFP91, and LIMD1) to the exquisitely selective degradation of CK1α;; and IKZF2. Beyond expanding the chemical landscape for intractable targets, our indazolone based MGDs exhibit favorable pharmacokinetic properties, offering robust promise for therapeutic development. Collectively, the remarkable tunability and exceptional neo-substrate programmability of the indazolone based platform provide a highly transformative blueprint for next-generation MGD discovery, enabling systematic exploration of the vast CRBN-accessible proteome. Furthermore, as superior CRBN ligands, this platform holds immense potential for PROTAC discovery to systematically address previously intractable targets.