Molecular Editing in Protein Degradation: From a Dual NSD2/GSPT1 Degrader to an NSD2-Selective PROTAC and a GSPT1-Selective Molecular Glue
- 1University of Michigan
Abstract
Both NSD2 and GSPT1 represent compelling targets for anti-cancer drug discovery. Herein, we carried out single-atom modification of LLC0424, an NSD2 degrader with GSPT1 neosubstrate engagement, to yield two structurally analogous molecules with divergent modes of action: 424-ND, an NSD2-selective degrader, and 424-GD, a GSPT1-selective degrader. 424-ND drove selective NSD2 degradation and suppressed androgen receptor (AR) signaling in prostate cancer cells. 424-GD induced selective degradation of GSPT1 and upregulated the integrated stress response markers ATF4 and ATF3. Biolayer interferometry revealed distinct ternary complex cooperativity profiles in the presence of NSD2 or GSPT1, which directly correlate with the observed biased degradation activity. Molecular dynamics and metadynamics simulations showed that the compounds adopt distinct low-energy conformational ensembles with different spatial orientations, likely underlying their divergent cooperativity and selectivity. These findings demonstrate that minimal structural alteration permits precision control over degrader target selectivity, while furnishing selective chemical probes for NSD2 and GSPT1.
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BibTeX
@misc{shen2026molecular,
title = {{Molecular Editing in Protein Degradation: From a Dual NSD2/GSPT1 Degrader to an NSD2-Selective PROTAC and a GSPT1-Selective Molecular Glue}},
author = {W. Shen and Y. Liu and L. Liu and Y. Liu and Y. Zhang and Y. Chen and Z. Zhou and A. Zhang and H. Shen and F. Zhou and W. Huang and X. Ren and A. Parolia and Y. Xu and Y. Zhou and Z. Wang and A. M. Chinnaiyan and K. Ding},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.09.750440},
url = {https://www.biorxiv.org/content/10.64898/2026.09.09.750440v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Molecular Editing in Protein Degradation: From a Dual NSD2/GSPT1 Degrader to an NSD2-Selective PROTAC and a GSPT1-Selective Molecular Glue
AU - W. Shen
AU - Y. Liu
AU - L. Liu
AU - Y. Liu
AU - Y. Zhang
AU - Y. Chen
AU - Z. Zhou
AU - A. Zhang
AU - H. Shen
AU - F. Zhou
AU - W. Huang
AU - X. Ren
AU - A. Parolia
AU - Y. Xu
AU - Y. Zhou
AU - Z. Wang
AU - A. M. Chinnaiyan
AU - K. Ding
PY - 2026
DA - 2026/09/09
PB - bioRxiv
DO - 10.64898/2026.09.09.750440
UR - https://www.biorxiv.org/content/10.64898/2026.09.09.750440v1
AB - Both NSD2 and GSPT1 represent compelling targets for anti-cancer drug discovery. Herein, we carried out single-atom modification of LLC0424, an NSD2 degrader with GSPT1 neosubstrate engagement, to yield two structurally analogous molecules with divergent modes of action: 424-ND, an NSD2-selective degrader, and 424-GD, a GSPT1-selective degrader. 424-ND drove selective NSD2 degradation and suppressed androgen receptor (AR) signaling in prostate cancer cells. 424-GD induced selective degradation of GSPT1 and upregulated the integrated stress response markers ATF4 and ATF3. Biolayer interferometry revealed distinct ternary complex cooperativity profiles in the presence of NSD2 or GSPT1, which directly correlate with the observed biased degradation activity. Molecular dynamics and metadynamics simulations showed that the compounds adopt distinct low-energy conformational ensembles with different spatial orientations, likely underlying their divergent cooperativity and selectivity. These findings demonstrate that minimal structural alteration permits precision control over degrader target selectivity, while furnishing selective chemical probes for NSD2 and GSPT1.
ER -