MI-77301

Protein target name:

MDM2

Mechanism of action:

Antagonist

Recommended Concentration for use in cells:

1-10 uM

Probe Availability

MedChem Express (1303607-60-4)

Abcam (1303607-60-4)

Cayman (1303607-60-4)

Probe Information

Target and Probe Information

Target Details

Target class:

ACTFS, HDMX, hdm4

Probe Details

Chemical Probes Portal ID:

CPP1591

Probe alias:

SAR405838

PubChem CID:

53476877

ChEMBL ID:

CHEMBL2381408

SMILES string:

O=C([C@H](N[C@H]1CC(C)(C)C)[C@H](C2=CC=CC(Cl)=C2F)[C@@]31C(NC4=C3C=CC(Cl)=C4)=O)N[C@@H]5CC[C@@H](O)CC5

InChi Key:

IDKAKZRYYDCJDU-AEPXTFJPSA-N

Orthogonal probe:

RO5353AM-6761AMG232

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

0.88 nM

Potency assay:

Fluorescence polarization binding assay with MDM2 protein and p53 peptide.

Off target activity

Potency assay (off target):

At 10 uM, MI-77301 did not bind MDMx as assessed by biolayer interferometry.

Probe Selectivity in Vitro:

At 10 uM, MI-77301 showed minimal interaction with BCL2, BCLXL, MCL1, beta-catenin and minimal activity against another ~200 enzymes and proteins.

In cell validation

On target activity in cells

Potency in cells:

IC50

0.092 uM

Potency assay (cells):

In SJSA-1 cells, MI-77301 inhibited cell growth. Comparable results were found in multiple cell lines that express p53.

Target engagement assay (cells):

In SJSA-1 cells, MI-77301 dose-dependently increased MDM2, p21 and PUMA RNA levels (but not p53 RNA levels), p53, p21, and MDM2 protein levels, and led to apoptosis. In multiple other cancer cell lines (leukemia, prostate cancer, colon cancer), the compound had comparable effects on p53 protein expression.

In vivo validation

Organism:

Female Balb/c nude mice

Dose:

25-200 mg/kg

Route of delivery:

Oral

Organ of Interest

Organ (O):

SJSA-1 xenografts

Target engagement assay:

In xenografts, MI-77301 dose-dependently increased p21 and PUMA RNA and increased p21, MDM2 and p53 protein expression. Comparable effects on p53 protein expression were obtained in multiple types of xenografts.

Primary Reference

Reference (doi):

10.1158/0008-5472.CAN-14-0799

Reference (PMID):

25145672

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

MI-77301 (synonym SAR405838) is a highly potent and selective MDM2 inhibitor (Ki=0.88 nM). MI-77301 inhibits the cell growth of cancer cell lines like p53 wild-type osteosarcoma SJSA-1 cell line (IC50=92 nM). The in vivo efficacy of the compound was shown in particular in the SJSA-1 osteosarcoma xenograft model.

Aug 9 2017 - 1:48pm

This probe is the result of extensive chemistry optimization over the last 10 years. The original compound was a rationally designed inhibitor of the interaction between p53 and MDM2, but it had liabilities that prevented clinical development. This latest compound appears to be outstanding in both cells and a variety of mouse xenograft cancer models.

Aug 18 2017 - 4:27pm

MI-77301

Probe Availability

Probe Information

Target Details

ACTFS, HDMX, hdm4

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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MI-77301

Probe Availability

Probe Information

Target Details

ACTFS, HDMX, hdm4

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?