| 生化机理 |
Description:
IC50 Value: 1.1 nM (BCL-XL) [1]
The prosurvival BCL-2 family protein BCL-XL is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. The optimized compound, WEHI-539, has high affinity (subnanomolar) and selectivity for BCL-XL and potently kills cells by selectively antagonizing its prosurvival activity.
WEHI-539 has a high affinity for BCL-XL (IC50 = 1.1 nM). WEHI-539 interacts with residues in the P4 pocket and adopts a distinct binding mode compared to ABT-737. WEHI-539 induces apoptosis in MEFs only if they lack MCL-1 supports the notion that cell killing induced by WEHI-539 is due to direct inhibition of BCL-XL. Accordingly, restoring expression of MCL-1 in mcl-1 knockout cells renders them highly resistant to WEHI-539. WEHI-539 could only kill cells that contained BAK (Fig. 6b). This observation was confirmed in MEFs where both the amount and activity of MCL-1 were abrogated by expression of its natural and selective BH3-only ligand NOXA. Cytochrome c release and caspase-3 processing confirmed that WEHI-539 induces apoptosis in BAX-deficient MEF cells expressing BIM2A but not in their BAK-deficient counterparts. Remarkably, WEHI-539 efficiently triggered the killing of platelets purified from mice or humans in culture.
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