gossypol-acetic-acid and navitoclax

B-cell lymphoma 2 (Bcl-2) is a regulator protein involved in apoptosis. In the past few decades, this protein has been demonstrated to have high efficacy in cancer therapy, and several approaches targeting Bcl-2 have been tested clinically (e.g., oblimersen, ABT-737, ABT-263, obatoclax mesylate, and AT-101). This review reports potential Bcl-2 inhibitors according to current information on their underlying mechanism and the results of clinical trials. In addition, the function and mechanisms of other potentially valuable Bcl-2 inhibitors that did not show efficacy in clinical studies are also discussed. This summary of the development of Bcl-2 inhibitors provides worthwhile viewpoints on the use of biomedical approaches in future cancer therapy.

Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Gossypol; Humans; Lymphoma, B-Cell; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Thionucleotides

The failure of apoptosis (programmed cell death) underpins the development of many tumors and often renders them resistant to cytotoxic therapies. In hematologic malignancies, this impairment of apoptosis is often caused by overexpression of the pro-survival protein BCL2. Because abnormally high levels of BCL2 sustain these tumors, there has been much interest in targeting BCL2 as a novel approach to treating various hematologic malignancies. One such approach is the development of BH3 mimetic compounds, small molecules that mimic the action of the BH3-only proteins, natural antagonists of BCL2 and its pro-survival relatives. These compounds act by restoring the ability of a cell to undergo apoptotic cell death. Some of them have shown very encouraging results in early-phase clinical trials that are currently underway, particularly in patients with chronic lymphocytic leukemia and some non-Hodgkin lymphomas, diseases marked by BCL2 overexpression. In this review, we discuss the rationale behind targeting BCL2, highlight the recent findings from clinical trials, and pinpoint the next steps in the clinical development of this interesting and promising class of targeted agents, particularly for the treatment of lymphoid malignancies.

Topics: Aniline Compounds; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Gossypol; Hematologic Neoplasms; Humans; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides

Topics: Antiviral Agents; Dengue Virus; Drug Repositioning; Molecular Docking Simulation; Neoplasms; Peptide Hydrolases; Protease Inhibitors; Structure-Activity Relationship; Viral Nonstructural Proteins

Despite real advances made in chemoimmunotherapy, chronic lymphocytic leukemia (CLL) is still an incurable disease. New therapeutic strategies based on the restoration of the cell death program seemed relevant. Some members of the Bcl-2 family are critical players in the defective apoptotic program in CLL cells and/or targets of apoptosis inducers in vitro. The concept of BH3 mimetics has led to the characterization of small molecules mimicking proapoptotic BH3-only members of the Bcl-2 family by their ability to bind and antagonize the prosurvival members. Some putative or actual BH3 mimetics are already being tested in clinical trials with somewhat promising results. However, none of them has a high enough interaction affinity with Mcl-1, a crucial antiapoptotic factor in CLL. It has been suggested that resistance to BH3 mimetics can be overcome by using inhibitors of Mcl-1 expression. An alternative and more direct strategy is to design mimetics of the Noxa BH3 domain, which is a specific antagonistic Mcl-1 ligand. The development of such Noxa-like BH3 mimetics, capable of directly interacting with Mcl-1 and efficiently neutralizing its antiapoptotic activity, is extremely important to evaluate their impact on the clinical outcome of patients with CLL.

Topics: Aniline Compounds; Apoptosis; Biomimetic Materials; Gossypol; Humans; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides