Venetoclax bound to BCL-2

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Venetoclax is an anti-cancer medication that zeroes in on the apoptosis pathway within cancer cells. Cancer cells are characterized by high levels of BCL-2, a pro-survival protein that prevents apoptosis by binding BH3 proteins, which detect cellular stress, and BAX and BAK proteins, which induce apoptosis. BCL-2 binds these proteins to a large hydrophobic groove on its surface with subpockets P1-P4. Venetoclax works as an antagonist by binding the hydrophobic groove of BCL-2 and blocking its interaction with BH3. It shares similarities with previous BH3 mimetic drugs but lacks their toxic off-target effects, making it one of the first small molecule medications to treat cancer by directly blocking protein-protein interactions. Venetoclax binds to the BCL-2 hydrophobic groove through various groups, including a 4-chlorophenyl group attached to the P2 subpocket, a piperazine group bound to the shallower groove between the P2 and P4 pockets, and an azaindole group bound in the P4 subpocket.