GSPT1/2 Degraders (SJ-20-0040)

St. Jude Reference #SJ-20-0040

Description

While the PROTAC approach to find small-molecules by targeting protein degradation benefits from rational design, the discovery of small-molecule degraders relies mostly on phenotypic screening and retrospective target identification efforts. Researchers at St. Jude recently published on the design, synthesis, and screening of a large diverse library of thalidomide analogues against a panel of patient-derived leukemia and medulloblastoma cell lines. These efforts led to the discovery of SJ6986, a potent and novel GSPT1/2 degrader displaying selectivity over classical IMiD neosubstrates, and a high oral bioavailability in mice. This compound, administered orally at 1 mg/kg dose, induced selective degradation of GSPT1 and showed a high anti-tumor efficacy in a patient-derived xenograft model of acute lymphoblastic leukemia.

Keywords

Phenotypic screening, retrospective target identification, library of thalidomide analogues, leukemia, medulloblastoma, GSPT1, GSPT2 degrader, oral bioavailability, anti-tumor

Grant Patents or Published Applications

Provisional application pending.

Related Scientific References

Nishiguchi G. et al. “Identification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1/2 Degraders from a Focused Library of Cereblon Modulators” J Med Chem. 2021 Jun 10;64(11):7296-7311. doi: 10.1021/acs.jmedchem.0c01313. Epub 2021 May 27.

Licensing Opportunities

More information is available under a confidentiality agreement. We are offering for license the molecules which showed anti-proliferative efficacy in multiple cancer cell lines, mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1 (also named eRF3a) for the development of cancer therapies.

Contact the Office of Technology Licensing (Phone: 901-595-2342, Fax: 901-595-3148) for more information.