LAUSR

Apoptosis is one of the major mechanisms exhibited in response to cell death and induction of apoptosis in tumour cells signifies a potential target for cancer therapy. Bcl-2 family proteins play a key role in regulation of the apoptotic pathway. Bcl-2 overexpression is commonly associated with various cancers including breast cancer, prostate cancer, B-cell lymphomas and colorectal adenocarcinomas etc. Thus, Bcl-2 is a novel anti-cancer target attracting medicinal chemists across the globe. Research investigations underlying Bcl-2 target have resulted in the generation of small molecule inhibitors, named as 'BH3-mimetics' (Bcl-2 homology 3 mimetics). These drugs display binding to pro-survival Bcl-2 proteins resulting in actuation of apoptosis of cancer cells. The first BH3 mimetics discovered as an outcome of structure-based drug design and Nuclear Magnetic Resonance (NMR)-based screening was ABT-263, an N-acylsulfonamide analogue. Thrombocytopenia a major dose-limiting toxicity, associated with ABT-263 had provoked the invention of a highly selective Bcl-2 inhibitor venetoclax. Several Bcl-2 inhibitors as small molecules are under clinical development and the results indicated that these molecules alone or in combination could be of potential application in cancer therapy. This review summarizes an up to date knowledge of the available small molecule inhibitors, their discovery, synthesis, current clinical and pre-clinical status.