MD-224

Degrader (PROTAC) of MDM2

Structure

Information

Protein target names: MDM2

Mechanism of action: Degrader (PROTAC)

Recommended in-cell concentration:
up to 30 nM

Reviewer recommended in-cell concentration: In certain cell lines (e.g, MV411), concentrations > 30 nM may be needed to achieve complete degradation of MDM2 after treatment for 2h.

In Vitro Validations

Uniprot ID: Q00987
Target Class: Other post-translational modification
Target SubClass: E3 ubiquitin ligase
Potency: Ki
Potency Value: 0.16 nM
Potency Assay: Fluorescence Polarization-Based (FP-Based)
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: partial, limited to linker
Target aliases:
E3 ubiquitin-protein ligase Mdm2, MDM2, MDM2_HUMAN ...

DOI Reference: 10.1021/acs.jmedchem.8b00909

Uniprot ID: Q00987
Target Class: Other post-translational modification
Target SubClass: E3 ubiquitin ligase
Potency: IC50
Potency Value: 4.4 nM
Potency Assay: Protein Binding Assay, Mi-1061 binding MDM2
PDB ID for probe-target interaction (3D structure): --
Target aliases:
E3 ubiquitin-protein ligase Mdm2, MDM2, MDM2_HUMAN ...

DOI Reference: 10.1021/acs.jmedchem.8b00909

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

For degrader molecules, selectivity is often assessed through proteomic studies that explore the relative stability of the presumed target (here MDM2) compared to other possible targets. Although that standard has not, at present, been met for MD-224, other ways of rigorously addressing target engagement and selectivity have been reported.

(last updated: 9 Feb 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

MG-277 has also been described as an optimized MDM2 degrader modified from MD-222. Ref: https://doi.org/10.1016/j.apsb.2020.01.003
 

(last updated: 18 Feb 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

MD-224 displays potent and rapid degradation of MDM2 in cells at low nanomolar concentrations. There is indirect evidence of binding to CRBN through lenalidomide competitive binding assays. Two compounds known as compound 21 and 22 can serve as inactive negative controls. No proteome-wide experiments were reported to investigate off-target effects. MD-224 was well-characterized in cells and in vivo and displayed p53-dependent cytotoxicity in several cancer cell lines. While MG-277 is proposed as an orthogonal probe, MG-277 may not efficiently degrade MDM2 and is also a potent degrader of GSPT1.

(last updated: 21 Mar 2022 )