MD-224

Degrader (PROTAC) of MDM2

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

MDM2

Degrader (PROTAC)

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

DOI - 10.1021/acs.jmedchem.8b00909

Probe Availability:

MedChemExpress

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

Off-Target Selectivity Assesments

Potency assay, off target (cells): Cell Growth Inhibition Activity

Probe Selectivity in Cell:

Cell Growth Inhibition Activity of MD-224 in a Panel of Human AML or ALL Cell Lines MOLM-13 7.3 nM, OL-14, 10.5 nM, SIG-M5 19.8 nM, ML-2 4.4 nM, OCL-AML-5 33.1 nM, mono-Man-6 >10 uM, KG-1 >10 uM. MD-224 are highly selective over leukemia cell lines with mutated p53.

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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 )