WEHI-539

BH3 mimetic of BCL2L1

Structure

SERP Rating

In Cells

(1 ratings)

In Model Organisms

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Probe WEHI-539 is in the process of SERP review.

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Information

BCL2L1

BH3 mimetic

100 nM - 1 uM

Probe Availability:

In Vitro Validations

Uniprot ID: Q07817

Target Class: Other

Target SubClass: Apoptosis regulator

Potency: Kd

Potency Value: 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.

Target aliases:

Bcl-2-like protein 1, BCLX, BCL2L, BCL2L1, B2CL1_H ...

DOI Reference: 10.1038/nchembio.1246

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency end-point : KD BCL-2: >750 nM, BCL-W: >550 nM, MCL-1: >550 nM, A1: >550 nM

Potency assay (off target): Direct binding assay by SPR.

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.

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP 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.

(last updated: 3 Aug 2017 )