Targeting BCL-2 in Hematologic Malignancies.

Resistance to apoptosis is one of the hallmarks of cancer and members of the B-cell lymphoma 2 (BCL-2) family of proteins are central regulators of apoptosis. Many cancers become resistant to chemotherapy and apoptosis by up-regulating BCL-2 and other family members, making these proteins attractive targets for cancer therapy. Venetoclax is an orally administered, small-molecule apoptosis stimulant that targets BCL-2 proteins by acting as a BCL-2 homology domain 3 (BH3) mimetic. The drug is approved in the USA and EU as a monotherapy for the for the treatment of certain patients with chronic lymphocytic leukemia (CLL) and is in phase III clinical development for multiple myeloma (MM), and in phase II or I/II clinical trials for acute myeloid leukemia, and several B-cell malignancies, including diffuse large B-cell lymphoma, Waldenstrom's macroglobulinaemia, follicular lymphoma, and mantle-cell lymphoma.