Selective Degradation of GSPT1 by Cereblon Modulators Identified via a Focused Combinatorial Library

ACS Chem Biol. 2020 Oct 16;15(10):2722-2730. doi: 10.1021/acschembio.0c00520. Epub 2020 Sep 28.


Cereblon (CRBN) is an E3 ligase adapter protein that can be reprogrammed by imide-class compounds such as thalidomide, lenalidomide, and pomalidomide to induce the degradation of neo-substrate proteins. In order to identify additional small molecule CRBN modulators, we implemented a focused combinatorial library approach where we fused an imide-based CRBN-binding pharmacophore to a heterocyclic scaffold, which could be further elaborated. We screened the library for CRBN-dependent antiproliferative activity in the multiple myeloma cell line MM1.S and identified five hit compounds. Quantitative chemical proteomics of hit compounds revealed that they induced selective degradation of GSPT1, a translation termination factor that is currently being explored as a therapeutic target for the treatment of acute myeloid leukemia. Molecular docking studies with CRBN and GSPT1 followed by analogue synthesis identified a possible hydrogen bond interaction with the central pyrimidine ring as a molecular determinant of hit compounds' selectivity. This study demonstrates that a focused combinatorial library design, phenotypic screening, and chemical proteomics can provide a suitable workflow to efficiently identify novel CRBN modulators.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Hydrogen Bonding
  • Molecular Docking Simulation
  • Peptide Termination Factors / chemistry
  • Peptide Termination Factors / metabolism*
  • Protein Binding
  • Proteolysis / drug effects*
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology*
  • Thalidomide / analogs & derivatives*
  • Thalidomide / metabolism
  • Thalidomide / pharmacology*
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • CRBN protein, human
  • Peptide Termination Factors
  • Small Molecule Libraries
  • peptide-chain-release factor 3
  • Thalidomide
  • Ubiquitin-Protein Ligases