WEHI-539

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.

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.