BCL2 is a pro-survival protein, crucial on regulating the mitochondrial pathway to apoptosis. It exerts its function by kidnapping a family of pro-apoptotic proteins, that includes the effectors of apoptosis BAX and BAK. This interaction takes place between the BCL2 homology 3 motif of the apoptotoic proteins and a BH3 binding groove present in BCL2.
In patients with acute lymphocytic leukemia, white blood cells have lost their abiity to enter both extrinsic apoptosis (triggered by extracellular “death” ligands) and intrinsic apoptosis (intracellular pathways), therefore leading to an uncontrolled, clonal accumulation of cancerous B cells. This is caused by an overexpression of pro-survival proteins, like BCL2.
Venetoclax is a BH3 mimetic molecule that works as an antagonist binding the BH3 binding groove in BCL2, kidnapping it and allowing the pro-apoptotic proteins to activate the cell death machinery.
This model shows the main interactions that take place between Venetoclax and BCL2.
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