---
title: "Molecular Editing Produces an NSD2-Selective PROTAC and a GSPT1-Selective Molecular Glue"
id: "biorxiv-23-molecular-editing-in-protein-degradation-from-a-dual-nsd2-gspt1-degrader-to-an"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-23-molecular-editing-in-protein-degradation-from-a-dual-nsd2-gspt1-degrader-to-an"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.09.750440v1?rss=1"
published_at: "2026-09-13T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Molecular Editing Produces an NSD2-Selective PROTAC and a GSPT1-Selective Molecular Glue
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-23-molecular-editing-in-protein-degradation-from-a-dual-nsd2-gspt1-degrader-to-an
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.09.750440v1?rss=1)
- **Published At:** 2026-09-13T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study applies **molecular editing** to repurpose an existing dual NSD2/GSPT1 degrader (LLC0424) into two structurally related compounds with distinct mechanisms: 424-ND and 424-GD. - 424-ND functions as a **PROTAC** that selectively degrades **NSD2** in a CRBN- and proteasome-dependent manner and suppresses androgen receptor (AR) signaling in prostate cancer cells. - 424-GD behaves as a **molecular glue** that selectively induces degradation of **GSPT1** and strongly upregulates integrated stress response markers **ATF4** and **ATF3**. - Biolayer interferometry experiments showed different ternary complex cooperativity profiles when NSD2 or GSPT1 were present, correlating with biased degradation outcomes. - Molecular dynamics and metadynamics simulations indicated the two compounds occupy distinct low-energy conformational ensembles with different spatial orientations, which likely explain divergent cooperativity and selectivity. - The work delivers selective chemical probes for **NSD2** and **GSPT1** and demonstrates that molecular editing can be a generalizable strategy to tune selectivity in targeted protein degradation. - Competing interests reported: K.D. advises biotech companies and A.M.C. has founded and advises several companies; funders include Chinese national and academy programs. - The paper is a preprint posted on bioRxiv and provides no additional clinical recommendations or in vivo efficacy or safety data in the abstract.
## Clinical Analysis & Structured Key Points
Molecular Editing in Protein Degradation: From a Dual NSD2/GSPT1 Degrader to an NSD2-Selective PROTAC and a GSPT1-Selective Molecular Glue | bioRxiv Skip to main content New Results Molecular Editing in Protein Degradation: From a Dual NSD2/GSPT1 Degrader to an NSD2-Selective PROTAC and a GSPT1-Selective Molecular Glue Weizhong Shen , Yihan Liu , Lianchao Liu , Yingfan Liu , Yan Zhang , Yihan Chen , Zhiyi Zhou , Angela Zhang , Hui Shen , Fengtao Zhou , Weixue Huang , Xiaomei Ren , Abhijit Parolia , Yong Xu , Yang Zhou , Zhen Wang , Arul M. Chinnaiyan , Ke Ding doi: https://doi.org/10.64898/2026.09.09.750440 Weizhong Shen 1 Shanghai Institute of Organic Chemistry; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yihan Liu 2 University of Michigan; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lianchao Liu 1 Shanghai Institute of Organic Chemistry; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yingfan Liu 3 Jinan University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yan Zhang 4 Guangdong Pharmeceutical University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yihan Chen 1 Shanghai Institute of Organic Chemistry; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Zhiyi Zhou 1 Shanghai Institute of Organic Chemistry; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Angela Zhang 2 University of Michigan; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hui Shen 5 Chinese Academy of Sciences Find this author on Google Scholar Find this author on PubMed Search for this author on this site Fengtao Zhou 3 Jinan University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Weixue Huang 1 Shanghai Institute of Organic Chemistry; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Xiaomei Ren 1 Shanghai Institute of Organic Chemistry; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abhijit Parolia 2 University of Michigan; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yong Xu 4 Guangdong Pharmeceutical University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yang Zhou 3 Jinan University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Zhen Wang 1 Shanghai Institute of Organic Chemistry; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Arul M. Chinnaiyan 2 University of Michigan; Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: arul{at}med.umich.edu Ke Ding 1 Shanghai Institute of Organic Chemistry; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Info/History Metrics Supplementary material Preview PDF Abstract Molecular editing, rooted in synthetic chemistry, has emerged as a powerful tool for structure optimization in medicinal chemistry but remains underutilized in targeted protein degradation. Here, we demonstrate the utility of molecular editing by repurposing the NSD2 degrader LLC0424 with GSPT1 neosubstrate engagement to generate two structurally analogous molecules with divergent modes of action: 424‑ND, a PROTAC selective for NSD2, and 424‑GD, a selective GSPT1 molecular glue. 424‑ND drove NSD2 degradation selectively in a CRBN- and proteasome-dependent manner and functionally suppressed androgen receptor (AR) signaling in prostate cancer cells. 424‑GD induced selective degradation of GSPT1 and robustly 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. Further 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 not only deliver highly selective chemical probes for NSD2 and GSPT1 but also demonstrate that molecular editing enables precision control over target selectivity, providing a generalizable strategy to tune selectivity in targeted protein degradation. Competing Interest Statement K.D. is an advisor for Kinoteck Therapeutics and NuLynx Therapeutics. A.M.C. co-founded and serves on the scientific advisory boards of Lynx Dx, Medsyn Pharma, NuLynx Therapeutics, and Esanik Therapeutics. Funder Information Declared National Natural Science Foundation of China , 82530108 , 22521104 National Key R&D Program of China , 2023YFE0119000 , 2023YFF1205104 , 2023YFC2506402 Strategic Priority Research Program of the Chinese Academy of Sciences , XDB1060000 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 13, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Chinnaiyan , Ke Ding bioRxiv 2026.09.09.750440; doi: https://doi.org/10.64898/2026.09.09.750440 Share This Article: Copy Citation Tools Molecular Editing in Protein Degradation: From a Dual NSD2/GSPT1 Degrader to an NSD2-Selective PROTAC and a GSPT1-Selective Molecular Glue Weizhong Shen , Yihan Liu , Lianchao Liu , Yingfan Liu , Yan Zhang , Yihan Chen , Zhiyi Zhou , Angela Zhang , Hui Shen , Fengtao Zhou , Weixue Huang , Xiaomei Ren , Abhijit Parolia , Yong Xu , Yang Zhou , Zhen Wang , Arul M. Chinnaiyan , Ke Ding bioRxiv 2026.09.09.750440; doi: https://doi.org/10.64898/2026.09.09.750440 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (7982) Biochemistry (18684) Bioengineering (14804) Bioinformatics (44277) Biophysics (22531) Cancer Biology (19650) Cell Biology (26810) Clinical Trials (138) Developmental Biology (13915) Ecology (20940) Epidemiology (2067) Evolutionary Biology (25400) Genetics (16131) Genomics (23441) Immunology (18640) Microbiology (42360) Molecular Biology (17992) Neuroscience (93155) Paleontology (695) Pathology (2974) Pharmacology and Toxicology (5075) Physiology (8087) Plant Biology (15944) Scientific Communication and Education (2094) Synthetic Biology (4546) Systems Biology (10201) Zoology (2381)
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