A-1210477

Reagent Authentication Certificate:

Chemical Probes Portal A-1210477.pdf

Protein target name:

MCL1

Mechanism of action:

BH3 mimetic

Recommended Concentration for use in cells:

Up to 3 uM

Probe Availability

Abcam (1668553-26-1)

MedChem Express (1668553-26-1)

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

Apotosis regulator

Subclass:

BCL2 family

HUGO ID:

HGNC:6943

Entrez gene ID:

4170

UNIPROT ID:

Q07820

Target alias:

BCL2 family apoptosis regulator, BCL2L3, EAT-ES, MCL1L, MCL1S, Mcl-1, TM, bcl2-L-3, mcl1/EAT, MCL1

Probe Details

Chemical Probes Portal ID:

CPP1287

PubChem CID:

66575373

ChEMBL ID:

CHEMBL3417704

SMILES string:

CC1=NN(C(=C1C2=CC=CC3=C2N(C(=C3CCCOC4=CC=CC5=CC=CC=C54)C(=O)O)CCN6CCOCC6)COC7=CC=C(C=C7)N8CCN(CC8)S(=O)(=O)N(C)C)C

InChi Key:

XMVAWGSQPHFXKU-UHFFFAOYSA-N

Orthogonal probe:

AMG 176S63845

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

0.454 nM

Potency assay:

Time-resolved Flourescence resonance energy transfer (TR-FRET) binding assay

Structure-activity relationship:

Yes, some. Several related compounds were reported in the original paper.

Off target activity

Potency (off target):

Off target protein and potency:

BCL2: 0.132 uM, BCLXL >0.660 uM

Potency assay (off target):

TR-FRET binding assay

In cell validation

On target activity in cells

Potency assay (cells):

In H29 cells, A-1210477 competed with BIM for MCL1 binding in co-IP assays (tested at 10 uM) and increased MCL1 protein but not RNA expression. In a coupled co-IP-ELISA assay, A-1210477 dose-dependently decreased BIM co-IP with and IC50 in the low uM range and disrupted NOXA-MCL1 interaction in a mammalian yeast two hybrid assay (IC50 ~1 uM). In cellular fluorescence localization assays, A-1210477 redistributed BIM labeled with mCherry from the mitochondria to the cytosol. In MCL1-dependent cells (H929 cells), A-1210477 induced apoptosis (IC50 <10 uM).

Target engagement assay (cells):

Indirect, coupled co-IP ELISA assay

Off target activity in cells

Potency assay, off target (cells):

A-1210477 had no affect on NOXA expression or on the localization of mCherry labeled BAD.

Primary Reference

Reference (doi):

10.1038/cddis.2014.561

Reference (PMID):

25590800

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

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

One might have expected rodent data on A-1210477 to have appeared by now, suggesting the experiments may not have worked. For cell-line studies, some of the less active analogues in PMID 25679114 would be useful specificity controls. Note, covalent probes for the same target have been reported in PMID: 27595327

Apr 14 2017 - 11:52am

There are much better probes for MCL-1 now available with significantly better cell potency and demonstrated in vivo efficacy, such as AMG-176 (disclosed in 2017 AACR and ACS; Ki = 50 pM), AZD5991 (disclosed in 2017 AACR; Ki = 130 pM), and S63845 (disclosed in 2016 Nature paper; Ki ~ 1 nM). I would not nominate A-1210477, as the other compounds are substantially better.

Apr 17 2017 - 1:07am

A-1210477

Probe Availability

Probe Information

Target Details

BCL2 family apoptosis regulator, BCL2L3, EAT-ES, MCL1L, MCL1S, Mcl-1, TM, bcl2-L-3, mcl1/EAT, MCL1

Probe Details

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

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A-1210477

Probe Availability

Probe Information

Target Details

BCL2 family apoptosis regulator, BCL2L3, EAT-ES, MCL1L, MCL1S, Mcl-1, TM, bcl2-L-3, mcl1/EAT, MCL1

Probe Details

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?