MG-277

Molecular Glue Degrader of GSPT1

Structure

Information

  • GSPT1
  • Molecular Glue Degrader
  • up to 1 uM

In Vitro Validations

Uniprot ID: P15170
Target Class: Other
Target SubClass: Translation Termination Factor
Potency: IC50
Potency Value: 67.5 nM
Potency Assay: FP competitive binding assay
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: Partial, limited to linker
Target aliases:
Eukaryotic peptide chain release factor GTP-bindin ...

DOI Reference: 10.1021/acs.jmedchem.9b00846

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

Unbiased proteomic analysis using the RS4;11 cells with wild-type p53 and the RS4;11/IRMI-2 cells carrying mutated p53 showed that, upon treatment with 0.1 μM of MG-277 for 3 h, GSPT1 protein is the only protein whose level is greatly reduced in both RS4;11 (5.3-fold, P < 0.001) and RS4;11/IRMI-2 (3.7-fold, P < 0.001) cell lines.

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SERP ratings and comments


SERP Ratings

In Cell Rating

SERP Comments:

MG-277 is a well-characterized degrader that depletes GSPT1 levels in several breast cancer and leukemia cell lines. The characterization included quantitative proteomic experiments (done at 100nM concentration and 3h treatment), which showed that GSPT1 was the major degradation target for MG-277. Additionally, phenotypic effects were shown to depend on the presence of the target and cereblon (CRBN), and depletion of GSPT1 levels upon MG-277 was shown to depend on the proteasome activity. The authors also describe a negative control compound (MC-024), which should be used in combination with MG-277. Please note that MG-277 retains binding to MDM2 (the target it was originally developed for but failed to degrade effectively), so some care needs to be taken when used to study GSPT1, especially if dealing with cells that express high levels of MDM2 relative to GSPT1. Finally, the original report includes compound MC-217 that has lost MDM2 binding. Therefore, it would be of benefit to characterize and validate this molecule further as it may represent a preferred probe given the lack of MDM2 binding.

(last updated: 7 Jul 2021 )