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

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.