WEHI-539

Protein target name:

BCL2L1

Mechanism of action:

BH3 mimetic

Recommended Concentration for use in cells:

100 nM - 1 uM

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

BCL2 family

Subclass:

Apoptosis regulator

HUGO ID:

HGNC:992

Entrez gene ID:

598

UNIPROT ID:

Q07817

Target alias:

BCLXL, bcl-xl, BCL2 like 1, BCL-XL/S, BCL2L, BCLX, Bcl-X, PPP1R52, BCLL2L1

Probe Details

Chemical Probes Portal ID:

CPP1254

Probe alias:

WEHI539

PubChem CID:

71297207

ChEMBL ID:

CHEMBL3342187

SMILES string:

C1CC2=C(C=C(C=C2)C3=NC(=C(S3)CCCOC4=CC=C(C=C4)CN)C(=O)O)/C(=N/NC5=NC6=CC=CC=C6S5)/C1

InChi Key:

JKMWZKPAXZBYEH-JWHWKPFMSA-N

Orthogonal probe:

A-1155463DT-2216A-1331852

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

1.4 nM

Potency assay:

Direct binding assay by SPR.

PDB ID for probe-target interaction (3D structure):

3ZLR

Structure-activity relationship:

Yes, see Nat Chem Biol paper.

Off target activity

Potency (off target):

Off target protein and potency:

BCL-2: >750 nM, BCL-W: >550 nMMCL-1: >550 nM, A1: >550 nM

Potency assay (off target):

Direct binding assay by SPR.

In cell validation

On target activity in cells

Potency assay (cells):

In mouse embryonic fibroblasts (MEFs), WEHI-539 induces apoptosis only in cells where MCL-1 is absent and not in cells where other BCL protein family members are absent. Restoration of MCL-1 expression renders MEFs resistant to WEHI-539. WEHI-539-induced apoptosis is dependent upon BAK but not BAX. In mouse and human platelets, WEHI-539 induces apoptosis.

Off target activity in cells

Potency assay, off target (cells):

As noted above, deletion of BCL2 protein family members other than MCL1 does not render MEFs sensitive to WEHI-539-induced apopotosis.

Primary Reference

Reference (doi):

10.1038/nchembio.1246

Reference (PMID):

23603658

External Resources

Available data:

GDSC2

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

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB Comments

WEHI-539 is an inhibitor of BCL-2 family proteins, binding potently and selectively to BCL-XL with an IC50 of ~1.1 nM. It was the first small molecule that selectively antagonizes the prosurvival activity of BCL-XL with nM potency. The discovery of WEHI-539 provided a valuable tool for shedding light on BCL-XL and apoptosis & tumor growth.

The solubility of this compound in DMSO is >10 mM; its molecular weight is 583.7, Log P = 6.86 (CLogP = 3.81), tPSA = 121.66. It is highly protein bound, likely has poor in vivo properties and has a labile and potentially toxic hydrazone moiety. It is currently one of three BCL-XL inhibitor probes being investigated (along with A-1155463 & A-1331852); In general, they all have similar physicochemical properties (but the two AbbVie compounds are devoid of the hydrazone moiety).

Platelets are known to depend on BCL-XL for their survival, and WEHI-539 induced apoptosis in both mouse (0-3 uM) and human platelets (log uM=0.01 to 100); this activity could be inhibited by a broad-spectrum caspase inhibitor (Nat Chem Biol 2013, 9,390-397). This compound is a valuable in-cell probe.

Unfortunately, because of its size, its protein binding affinity, its lipophilicity and, in general, poor physicochemical properties and the fact that it contains a hydrazone moiety, which will likely have stability issues in vivo, it will not be a good in vivo probe.

Aug 3 2017 - 5:04pm

WEHI-539 has a good potency (~1.4 nM) and a good selectivity over other BCL-2 family proteins. It is a good cellular probe as it induces apoptosis in both mouse and human platelets which is a biomarker for BCL-XL. It is not recommended for use in vivo due to poor physicochemical properties. Another BCL-XL (A-11155463) is more suitable as an in vivo probe due to lack of hydrazone moiety.

Mar 12 2020 - 12:04pm

WEHI-539

Probe Information

Target Details

BCLXL, bcl-xl, BCL2 like 1, BCL-XL/S, BCL2L, BCLX, Bcl-X, PPP1R52, BCLL2L1

Probe Details

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?

Search form

WEHI-539

Probe Information

Target Details

BCLXL, bcl-xl, BCL2 like 1, BCL-XL/S, BCL2L, BCLX, Bcl-X, PPP1R52, BCLL2L1

Probe Details

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?