2. Academic Validation
  3. SJPYT-195: A Designed Nuclear Receptor Degrader That Functions as a Molecular Glue Degrader of GSPT1

SJPYT-195: A Designed Nuclear Receptor Degrader That Functions as a Molecular Glue Degrader of GSPT1

  • ACS Med Chem Lett. 2022 Jul 15;13(8):1311-1320. doi: 10.1021/acsmedchemlett.2c00223.
Andrew D Huber 1,  Yongtao Li 1,  Wenwei Lin 1,  Annalise N Galbraith 1,  Ashutosh Mishra 2,  Shaina N Porter 3 4,  Jing Wu 1,  Rebecca R Florke Gee 1 5,  Wei Zhuang 1,  Shondra M Pruett-Miller 3 4,  Junmin Peng 2 6 7,  Taosheng Chen 1
Affiliations

Affiliations

  • 1 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 2 Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 3 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 4 Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 5 Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 6 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 7 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
PMID: 35978691 DOI: 10.1021/acsmedchemlett.2c00223
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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