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

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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Humans, Hydrogen Bonding, Molecular Docking Simulation, Peptide Termination Factors, Protein Binding, Proteolysis, Small Molecule Libraries, Thalidomide, Ubiquitin-Protein Ligases
ACS Chem Biol
Date: Dec. 16, 2019
Download Curated Data For This Publication
229378
Switch View:
  • Chemical Interactions 10