The Development of Novel Inhibitors of BCL2 Gene Expression as Anticancer Therape

Project Summary Evasion of apoptosis is a hallmark of cancer and is associated with oncogenesis, tumor maintenance, and resistance to conventional chemotherapy. BCL-2 was the first identified anti-apoptotic factor and is a member of the BCL-2 family of proteins that cooperate in the regulation of programmed cell death. BCL-2 plays a dominant role in the survival of multiple lymphoid malignancies and has consequently become an active target for drug discovery programs seeking to reactivate dormant apoptoticsignaling in cancer cells or enhance the activity of cytotoxic anticancer drugs. The only small-molecule-based approach has been to target the BH3 binding domain of Bcl-2, thereby blocking interaction with other pro-apoptotic Bcl-2 family members. However,the recent suspension of the BH3 mimetic ABT-119 from clinical trials, due to the occurrence of tumor lysis syndrome, has cast some doubt over the potential safety of the BH3 mimetic approach and increased the need for alternative strategies to target BC