Drugs and Clinical Approaches Targeting the Antiapoptotic Protein: A Review

Abstract

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.

AhR and Cancer: from Gene Profiling to Targeted Therapy

“…Such a correlation analysis makes it possible to identify, among already available molecules, those that are adapted to the tumor type according to AhR level. For example, ABT-263 (Navitoclax), which targets the apoptosis inhibitor Bcl-2 [105], was more effective in lung-cancer cell lines that weakly express AhR (left panel of Fig. 4A).…”

Prostate apoptosis response-4 and tumor suppression: it’s not just about apoptosis anymore

“…Azmi et al demonstrated that nonpeptidic small-molecule inhibitors of Bcl-2 family proteins (apogossypolone and TW-37) induced Par-4-dependent inhibition of cell growth and induction of apoptosis in pancreatic cancer cells and inhibited tumor growth in xenograft animal model 113 . According to recent data, ~19 different Bcl-2 inhibitors (antibodies, small molecule drugs, and antisense oligonucleotides) are undergoing preclinical or clinical studies for the treatment of different cancers 110 . It will be interesting to evaluate whether some of these agents can induce Par-4.…”

Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?

“…29 The follow-up studies demonstrated that gossypol structurally behaves as a BH3-mimetic which can bind to Bcl-2 and Bcl-xl 30,31 and later AT-101 [(-)gossypol] became one of the first orally available Bcl-2 inhibitor that has entered the clinical trials. 32 Up until now, AT-101 has been investigated in more than 20 phase I/II and 1 Phase III clinical trial(s) as a single agent or in combination with other agents against multiple types of cancer (https://clinicaltrials.gov). Two phase II trials are still ongoing in China (CTR20150540, CTR20150541).…”