Many cancer cells maintain survival through over-expression of anti-apoptotic BCL-2 family proteins, making them compelling targets for the development of cancer therapeutics. However, disrupting protein-protein interactions, such as the BCL-2 or BCL‑XL interactions with pro-apoptotic BH3 proteins, has been a major challenge for the field. The BCL-2/BCL-XL inhibitor ABT-263 (navitoclax) has shown promising activity in the clinic but its efficacy has been limited by thrombocytopenia caused by BCL-XL inhibition. This clinical result led to the design of ABT-199/GDC-0199, a BCL-2-selective inhibitor that maintains efficacy in hematologic malignancies while sparing platelets. The challenging path to ABT-199/GDC-0199 will be presented, as will clinical data that represents validation of the hypothesis behind selectively targeting BCL-2. While ABT-199/GDC-0199 has helped establish the importance of targeting BCL-2 in hematologic malignancies, expression of BCL-XL has been linked with drug resistance and disease progression in multiple solid tumors. Efforts towards the development of novel BCL-XL-selective inhibitors will also be discussed.

Selective BCL-2 family inhibitors: Potential therapeutics and powerful research tools

250th National Meeting (2015)

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