ArticleACS medicinal chemistry letters2022
SJPYT-195: A Designed Nuclear Receptor Degrader That Functions as a Molecular Glue Degrader of GSPT1.
Article in ACS medicinal chemistry letters, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 31 citations in OpenAlex.
- Hide and seek: targeting nuclear receptor PXR with inhibitors and PROTACs to improve drug efficacy and safety.Expert opinion on therapeutic targets · 2026Article
- Advances in molecular glue degraders for targeted protein degradation: Focus on NEK7, WEE1, CDK2, GSPT1 and VAV1.Asian journal of pharmaceutical sciences · 2026Review
- Cancer Biology of GSPT1: Mechanisms and Targeted Therapy Opportunities of Molecular Glue Degraders.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- PROTAC repurposing uncovers a noncanonical binding surface that mediates chemical degradation of nuclear receptors.Nature communications · 2025Article
- Targeting pregnane X receptor with a potent agonist-based PROTAC to delay colon cancer relapse.Oncogenesis · 2025Article
- Discovery of PXR Antagonist MI891 and PXR Degrader MI1013 and Their Roles in Hepatic Gene Regulation.Journal of medicinal chemistry · 2025Article
- PROTAC-mediated activation, rather than degradation, of a nuclear receptor reveals complex ligand-receptor interaction network.Structure (London, England : 1993) · 2024Article
- First-in-Class Small Molecule Degrader of Pregnane X Receptor Enhances Chemotherapy Efficacy.Journal of medicinal chemistry · 2024Article
- Ligand flexibility and binding pocket malleability cooperate to allow selective PXR activation by analogs of a promiscuous nuclear receptor ligand.Structure (London, England : 1993) · 2023Article
- The F-box-only protein 44 regulates pregnane X receptor protein level by ubiquitination and degradation.Acta pharmaceutica Sinica. B · 2023Article
- Novel approaches to targeted protein degradation technologies in drug discovery.Expert opinion on drug discovery · 2023Review
- Accessing three-branched high-affinity cereblon ligands for molecular glue and protein degrader design.RSC chemical biology · 2023Article
- Structure-guided approach to modulate small molecule binding to a promiscuous ligand-activated protein.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Regulation of Nuclear Receptors PXR and CAR by Small Molecules and Signal Crosstalk: Roles in Drug Metabolism and Beyond.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- The importance of controls in targeted protein degradation: Determining mechanism.Methods in enzymology · 2023Article
- Review
- Regulation of PXR in drug metabolism: chemical and structural perspectives.Expert opinion on drug metabolism & toxicologyReview
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
We previously reported a specific inverse agonist (SPA70) of the nuclear receptor pregnane X receptor (PXR). However, derivatization of SPA70 yielded only agonists and neutral antagonists, suggesting that inverse agonism of PXR is difficult to achieve. Therefore, we sought to design proteolysis targeting chimeras (PROTACs) aimed at inducing PXR degradation. Conjugation of a SPA70 derivative to ligands of the E3 substrate receptor cereblon (CRBN) resulted in one molecule, SJPYT-195, that reduced PXR protein level in an optimized degradation assay described here. Further analysis revealed that SJPYT-195 was a molecular glue degrader of the translation termination factor GSPT1 and that GSPT1 degradation resulted in subsequent reduction of PXR protein. GSPT1 has recently gained interest as an anticancer target, and our results give new insights into chemical determinants of drug-induced GSPT1 degradation. Additionally, we have developed assays and cell models for PXR degrader discovery that can be applied to additional protein targets.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.