AM-6761

Antagonist of MDM2

Structure

Information

Protein target names: MDM2

Mechanism of action: Antagonist

Recommended in-cell concentration:
20 nM - 1 uM

In Vitro Validations

Uniprot ID: Q00987
Target Class: Other post-translational modification
Target SubClass: E3 ubiquitin ligase
Potency: IC50
Potency Value: 0.1 nM 0% HS; 0.8 nM 15% HS
Potency Assay: HTRF-based neutralization assay with and without Human Serum (HS)
PDB ID for probe-target interaction (3D structure): 4ODE
Structure-activity relationship: yes
Target aliases:
E3 ubiquitin-protein ligase Mdm2, MDM2, MDM2_HUMAN ...

DOI Reference: 10.1021/jm401911v

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

AM-6761 is broadly comparable to the previously reported compound AMG-232 in terms of high potency and robust effects in cells. AM-6761 would be a confirmatory molecule from the same chemical scaffold. High selectivity has been shown for MDM2 over MDMX, and for effects on cells expressing WT P53 over P53-deficient cells. Broader off-target selectivity data has not been published and would be beneficial to aid interpretation of the effects of the compound in wider cell-based screening. Pharmacokinetic and pharmacodynamics data support the use of AM-6761 in mouse models in vivo. AM-6761 shows lower efficacy (fewer tumour regressions at high dose) in xenograft tumours than AMG-232, which might, therefore, be preferred for in vivo studies.

(last updated: 23 Jun 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This is a good probe for cell and mouse studies, but it is probably less useful than related Amgen compounds that have entered human testing, such as AMG232. In a mouse xenograft SJSA-1 osteosarcoma tumor model the compound caused 6% tumor reduction at the highest dose, 50 mg/kg.

(last updated: 27 Jun 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This is a high quality probe derived from AMG232 and broadly comparable to that clinical agent, with similar potency and in vivo anti-tumor activity in an SJSA-1 mouse model. Publications of AMG232 and AM-6761 are highly similar in assays and format and can be compared for further details. This compound is very selective for MDM2 compared to MDMX (IC50>100 uM). Due to chemical similarity to AMG232, this compound could be viewed as a confirmatory molecule with the same scaffold.

(last updated: 6 Jul 2017 )