MG-277

Protein target name:

GSPT1

Mechanism of action:

DegraderPROTACMolecular Glue

Recommended Concentration for use in cells:

up to 1 uM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Subclass:

Translation Termination Factor

HUGO ID:

HGNC:4621

Entrez gene ID:

2935

UNIPROT ID:

P15170

Target alias:

GST1; ETF3A; eRF3a; 551G9.2

Probe Details

Chemical Probes Portal ID:

CPP2128

Probe alias:

PROTAC, Molecular Glue

PubChem CID:

139600332

ChEMBL ID:

CHEMBL4449512

SMILES string:

ClC1=CC=C2C(NC([C@@]23C4(N[C@H]([C@@H]3C5=CC=CC(Cl)=C5F)C(NCCCCCC6=C(C7=CC=C6)CN(C7=O)C8C(NC(CC8)=O)=O)=O)CCCCC4)=O)=C1

InChi Key:

BANRYGZZIMCKNA-OYGJEQPESA-N

Orthogonal probe:

MC-024CC-90009

Physico-chemical properties

NMR:

1H NMR (400 MHz, methanol-d4): δ 7.65 (d, J = 7.3 Hz, 2H), 7.53–7.38 (m, 3H), 7.40–7.31 (m, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.10 (dt, J = 8.2, 2.4 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 5.19 (dt, J = 13.3, 5.5 Hz, 1H), 5.08 (d, J = 11.0 Hz, 1H), 4.75 (d, J = 11.0 Hz, 1H), 4.55–4.38 (m, 2H), 3.45–3.33 (m, 1H), 3.08–2.86 (m, 2H), 2.85–2.65 (m, 2H), 2.65–2.45 (m, 3H), 2.40–2.30 (m, 1H), 2.25–2.07 (m, 2H), 1.99–1.80 (m, 3H), 1.79–1.67 (m, 2H), 1.60–1.26 (m, 5H), 1.23–1.04 (m, 3H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

67.5 nM

Potency assay:

FP competitive binding assay

Structure-activity relationship:

Partial, limited to linker

Off target activity

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.

In cell validation

On target activity in cells

Potency in cells:

DC50IC50

1.3 nM (DC50)1.3 (R), 24.6 (MO), 7.9 (MV) nM

Potency assay (cells):

Proteomic Analysis/Protein Profiling, Cell Growth inhibition (cell lines used: RSA;11 (R), MOLM-13 (MO) MV411 (MV))

Phenotypic Control Experiment:

Co-treatment with an excess amount of lenalidomide (30 μM) effectively blocks the degradation of GSPT1 protein induced by MG-277 in both MDA-MB-231 and MDA-MB-468 cell lines. Efficient siRNA knock-down of CRBN in these two breast cancer cell lines also blocks the degradation of GSPT1 induced by MG-277.

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.9b00846

Reference (PMID):

31560543

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

1 review(s)

Rating for use in Model Organisms

no rating

SAB Members

SAB 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.

Jul 7 2021 - 12:29pm

MG-277

Probe Availability

Probe Information

Target Details

GST1; ETF3A; eRF3a; 551G9.2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

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MG-277

Probe Availability

Probe Information

Target Details

GST1; ETF3A; eRF3a; 551G9.2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?