Biology subjects

Nie, H.-J.

Publications and source records attributed to Nie, H.-J..

2 recordsLinked to original sources

bioRxiv2026

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 CK1 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.

biochemistry↗

bioRxiv2025

Visible-Light-Controlled Residue-Selective Cross-Linking for Deciphering Protein Complexes and Dynamic Protein-Protein Interactions in Live Cells

Cross-linking mass spectrometry (XL-MS) has emerged as an attractive technology for investigating protein complexes and protein-protein interactions (PPIs). However, commonly used cross-linking strategies present significant challenges for precise analysis of protein complexes and dynamic PPIs in native biological environments. Here we present the visible-light-controlled lysine-selective cross-linking (VL-XL) strategy for in-depth analysis of protein complexes and dynamic PPIs both in vitro and in live cells, building on light-induced primary amines and o-nitrobenzyl alcohols cyclization (PANAC) chemistry. We demonstrate that the VL-XL strategy effectively explores the dynamic dimerization of PD-L1 stimulated by exogenous modulators. Moreover, the VL-XL strategy successfully profiles the time-resolved EGF-stimulated EGFR interactome, providing valuable insights into the regulatory mechanisms of EGFR signaling and intracellular trafficking. Importantly, the VL-XL strategy efficiently deciphers the molecular glue (MG) induced dynamic PPIs and substrate profile of MG degrader, opening an innovative avenue for identifying neo-substrates. By harnessing the advantages of temporal controllability, good biocompatibility, and lysine selectivity, the VL-XL method simplifies MS data analysis and facilitates the acquisition of accurate structural information of protein complexes and the elucidation of elusive PPIs in live cells. Overall, the VL-XL strategy expands the XL-MS toolbox, and realizes in-depth analysis of protein complexes and dynamic PPIs, which will inspire innovative solutions for protein interactomes research and structural systems biology.

biochemistry↗