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Venetoclax, the first BCL-2 inhibitor for use in patients with chronic lymphocytic leukemia.

JS Venetoclax (Venclexta, AbbVie/Genentech) has a unique mechanism of action. It is the first drug in a novel class called BH3 mimetics. Venetoclax binds with high avidity to a particular protein, B-cell lymphoma 2 (BCL2), within the family of proteins inside a cell that regulate apoptosis. Venetoclax has an exquisite selectivity for BCL2. By binding to BCL-2 and inhibiting its normal function, venetoclax frees the proteins that would normally be bound to BCL-2 to initiate the apoptotic cascade. Venetoclax has been studied in several diseases. It has the greatest clinical activity in CLL. Overexpression of BCL-2 is a near-universal feature of CLL and intrinsic to the pathophysiology of this disease. A deletion on chromosome 13q that is very common in CLL removes a regulatory element, a microRNA, that normally functions to suppress the expression of BCL-2.