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
  • 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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