Pharmacological inhibition of Bax-induced cell death: Bax-inhibiting peptides and small compounds inhibiting Bax

Bax is an essential mediator of mitochondria-dependent programed cell death. Bax belongs to the Bcl-2 family of proteins and its activities are regulated through interaction with other member proteins in the Bcl-2 family. To date, several apoptosis-inducing drugs activating Bax have been developed, and some of them are already in the market as therapeutics against cancer. However, at present, there are no clinically effective pharmacological Bax inhibitors protecting essential cells. Previously, we developed Bax-Inhibiting Peptides (BIPs) that belong to the peptide group of Cell-Penetrating Peptides (CPPs). CPPs have the ability to deliver cargo molecules into the cell. In this review, we will describe the mechanism of action of BIPs together with the recent applications of BIPs in disease models in vitro and in vivo. However, BIPs have several limitations in their use to treat human diseases, and other types of Bax inhibitors need to be developed for future therapeutics. Recently, several groups reported the successful development of novel small compounds inhibiting Bax. We will review these Bax inhibitors to discuss current strategies to develop pharmacological Bax inhibitors. Impact statement Bax induces mitochondria-dependent programed cell death. While cytotoxic drugs activating Bax have been developed for cancer treatment, clinically effective therapeutics suppressing Bax-induced cell death rescuing essential cells have not been developed. This mini-review will summarize previously reported Bax inhibitors including peptides, small compounds, and antibodies. We will discuss potential applications and the future direction of these Bax inhibitors.