a-1155463 and Neoplasms

Apoptosis is the major mode of programmed cell death, which conduces to maintain tissue homeostasis, clearance of abnormal cells and development of organisms. Over the past two decades, great progress and significant clinical benefits in cancer treatment have been made by targeting Bcl-2 anti-apoptotic proteins. However, with the deep research of clinic, the therapeutic value of single target inhibitors is restricted due to the limited monotherapy activity, potential and complex drug resistance as well as monotherapy safety. This review focuses on recent advance in discovery of novel apoptosis inducers targeting Bcl-2 anti-apoptotic proteins aiming to overcome existing therapeutic limitations, and introduce the strategies and advanced technologies in the drug design and optimization.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Drug Design; Neoplasms; Proto-Oncogene Proteins c-bcl-2

The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics.

Topics: Administration, Oral; Aniline Compounds; Animals; Antineoplastic Agents; bcl-X Protein; Benzothiazoles; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Survival; Docetaxel; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Granulocytes; Humans; Isoquinolines; Kinetics; Mice; Neoplasm Transplantation; Neoplasms; Neutropenia; Neutrophils; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Taxoids; Thrombocytopenia