2. Academic Validation
  3. Identification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1/2 Degraders from a Focused Library of Cereblon Modulators

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.
Gisele Nishiguchi 1,  Fatemeh Keramatnia 1 2,  Jaeki Min 1,  Yunchao Chang 3,  Barbara Jonchere 4,  Sourav Das 1,  Marisa Actis 1,  Jeanine Price 1,  Divyabharathi Chepyala 1,  Brandon Young 1,  Kevin McGowan 1,  P Jake Slavish 1,  Anand Mayasundari 1,  Jamie A Jarusiewicz 1,  Lei Yang 1,  Yong Li 1,  Xiang Fu 1,  Shalandus H Garrett 1,  James B Papizan 5,  Kiran Kodali 6,  Junmin Peng 6 7 8,  Shondra M Pruett Miller 5,  Martine F Roussel 4,  Charles Mullighan 3,  Marcus Fischer 1 2 8,  Zoran Rankovic 1
Affiliations

Affiliations

  • 1 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 2 Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 3 Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 4 Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 5 Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 6 Center for Proteomics and Metabolomics, 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.
  • 8 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
PMID: 34042448 DOI: 10.1021/acs.jmedchem.0c01313
Abstract

Whereas the PROTAC approach to target protein degradation greatly benefits from rational design, the discovery of small-molecule degraders relies mostly on phenotypic screening and retrospective target identification efforts. Here, we describe 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 potent and novel GSPT1/2 degraders displaying selectivity over classical IMiD neosubstrates, such as IKZF1/3, and high oral bioavailability in mice. Taken together, this study offers compound 6 (SJ6986) as a valuable chemical probe for studying the role of GSPT1/2 in vitro and in vivo, and it supports the utility of a diverse library of CRBN Binders in the pursuit of targeting undruggable oncoproteins.

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