BDA-366 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

Overexpression of B cell lymphoma 2 (Bcl-2) proteins is associated with therapy resistance in various human cancers. Traditional approaches target the Bcl-2 homology (BH)3 domain of Bcl-2; however, the BH4 domain represents a superior therapeutic target in light of its unique structure and crucial involvement in many cellular functions. In this critical review, we focus on the structural and functional basis of targeting the BH4 domain of Bcl-2, and highlight the recent advances in drug discovery efforts toward small-molecule BH4 domain inhibitors (e.g. BDA-366). The proof-of-concept studies support the hypothesis that targeting the BH4 domain of Bcl-2 holds promise to offer a novel anticancer therapy through the induction of apoptosis and an increased potential to overcome therapeutic resistance.

Topics: Animals; Anthraquinones; Antineoplastic Agents; Ethanolamines; Humans; Neoplasms; Peptides; Protein Domains; Proto-Oncogene Proteins c-bcl-2

Topics: Anthraquinones; Apoptosis; Ethanolamines; Neoplasms; Proto-Oncogene Proteins c-bcl-2

Several cancer cell types, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL) upregulate antiapoptotic Bcl-2 to cope with oncogenic stress. BH3 mimetics targeting Bcl-2's hydrophobic cleft have been developed, including venetoclax as a promising anticancer precision medicine for treating CLL patients. Recently, BDA-366 was identified as a small molecule BH4-domain antagonist that could kill lung cancer and multiple myeloma cells. BDA-366 was proposed to switch Bcl-2 from an antiapoptotic into a proapoptotic protein, thereby activating Bax and inducing apoptosis. Here, we scrutinized the therapeutic potential and mechanism of action of BDA-366 in CLL and DLBCL. Although BDA-366 displayed selective toxicity against both cell types, the BDA-366-induced cell death did not correlate with Bcl-2-protein levels and also occurred in the absence of Bcl-2. Moreover, although BDA-366 provoked Bax activation, it did neither directly activate Bax nor switch Bcl-2 into a Bax-activating protein in in vitro Bax/liposome assays. Instead, in primary CLL cells and DLBCL cell lines, BDA-366 inhibited the activity of the PI3K/AKT pathway, resulted in Bcl-2 dephosphorylation and reduced Mcl-1-protein levels without affecting the levels of Bcl-2 or Bcl-xL. Hence, our work challenges the current view that BDA-366 is a BH4-domain antagonist of Bcl-2 that turns Bcl-2 into a pro-apoptotic protein. Rather, our results indicate that other mechanisms beyond switching Bcl-2 conformation underlie BDA-366's cell-death properties that may implicate Mcl-1 downregulation and/or Bcl-2 dephosphorylation.

Topics: Anthraquinones; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Calcium; Cell Line, Tumor; Cytosol; Dose-Response Relationship, Drug; Down-Regulation; Drug Screening Assays, Antitumor; Ethanolamines; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Liposomes; Lymphoma, Large B-Cell, Diffuse; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; Phosphorylation; Protein Conformation; Protein Domains; Proto-Oncogene Proteins c-bcl-2; Signal Transduction

Topics: Animals; Anthraquinones; Antineoplastic Agents; Apoptosis; Ethanolamines; Humans; Neoplasms; Peptides; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2