St. Jude Reference #SJ-22-0029
Researchers at St. Jude have designed, synthesized, and characterized a series of novel, potent, selective and structurally related compounds that modulate the transcriptional activity of human pregnane X receptor (hPXR), including agonists, antagonists, and inverse agonists; all with therapeutic implications. While activation of PXR by its agonists can be used to develop treatment for diseases such as inflammatory bowel disease (IBD), inhibition of PXR by its antagonists or inverse agonists can be used to prevent hPXR-mediated drug-resistance and drug-toxicity and improve drug efficacy, and none were available prior.
The PXR modulators are novel, potent, selective, and enabling generation of bi-functional compounds. The hPXR degrader is the first such compound. They also discovered a GSPT1 targeted degrader for broad antitumor activity (acute myeloid leukemia (AML), etc.) which is structurally novel.
The researchers believe these compounds have significant value for scientific research, and for developing the hPXR inhibitors and degrader as drugs to prevent therapy-related toxicities, drug-drug interactions, and drug resistance, and improve therapeutic efficacy and safety.
PROTAC, molecular glue, pregnane X receptor, GSPT1, acute myeloid leukemia
Granted patents or published applications
A provisional patent application has been filed.
Related scientific references
Li Y, Lin W, Chai SC, Wu J, Annu K, Chen T., “Design and Optimization of 1H-1,2,3-Triazole-4-carboxamides as Novel, Potent, and Selective Inverse Agonists and Antagonists of PXR.” J Med Chem. 2022 Dec 22;65(24):16829-16859.
Andrew D. Huber, Yongtao Li, Wenwei Lin, Annalise N. Galbraith, Ashutosh Mishra, Shaina N. Porter, Jing Wu, Rebecca R. Florke Gee, Wei Zhuang, Shondra M. Pruett-Miller, Junmin Peng, and Taosheng Chen; “SJPYT-195: A Designed Nuclear Receptor Degrader That Functions as a Molecular Glue Degrader of GSPT1;” ACS Medicinal Chemistry Letters 2022 13 (8), 1311-1320. DOI: 10.1021/acsmedchemlett.2c00223
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