BH3-mimetics: recent developments in cancer therapy

Abstract

The hopeful outcomes from 30 years of research in BH3-mimetics have indeed served a number of solid paradigms for targeting intermediates from the apoptosis pathway in a variety of diseased states. Not only have such rational approaches in drug design yielded several key therapeutics, such outputs have also offered insights into the integrated mechanistic aspects of basic and clinical research at the genetics level for the future. In no other area of medical research have the effects of such work been felt, than in cancer research, through targeting the BAX-Bcl-2 protein-protein interactions. With these promising outputs in mind, several mimetics, and their potential therapeutic applications, have also been developed for several other pathological conditions, such as cardiovascular disease and tissue fibrosis, thus highlighting the universal importance of the intrinsic arm of the apoptosis pathway and its input to general tissue homeostasis. Considering such recent developments, and in a field that has generated so much scientific interest, we take stock of how the broadening area of BH3-mimetics has developed and diversified, with a focus on their uses in single and combined cancer treatment regimens and recently explored therapeutic delivery methods that may aid the development of future therapeutics of this nature.

Keywords: Apoptosis; BH-3 mimetics; Bcl-xL-mimetics; Mcl1-mimetics; Nanoparticles; Noxa-mimetics; PUMA-mimetics; Smac-mimetics.

Fig. 1

The BH- and helical- domain composition of selected Bcl-2 family pro-apoptotic (red boxes), anti-apoptotic (blue boxes) and BH3-only (green boxes) members. The amino acid sequences of the human BH3-domains from BAX and BAK are highlighted (top left), below which are shown the amino acid sequences of the alpha helices 2–5 from the human Bcl-2 protein. For each of the proteins, the transmembrane domain is highlighted in orange and BH1–4 domains are respectively highlighted in blue, black, red and green for the relevant proteins

Fig. 2

The regulation of apoptosis by the BAX protein through mitochondrial outer membrane permeabilization (MOMP), and the modulation of this key steps by therapeutics. Key negative regulator Bcl-2, Bcl-xL and Mcl1 proteins (solid oval green boxes) for BAX (solid orange box) and their apoptosis inducing effects by cytochrome c release (solid yellow box and circles), caspase protein activation (solid red box) and apoptosis (solid purple box) are shown. The mimetics/inhibitors that can target anti−/pro-apoptotic protein interactions are highlighted as BH3-mimetics (outlined red box, red dots) and Mcl1 inhibitors (outlined green box, green dots), which either induce apoptosis of cells as mono-therapeutics or sensitize them to such effects during combined therapeutic targeting. The blue solid boxes (and small circles) highlight mitochondrial Smac/DIABLO, NOXA and PUMA, which bind the Inhibitor of Apoptosis Proteins (small green circles, IAPs) and the interactions of which can be inhibited by Smac-mimetics (blue outlined box and blue dots)

Fig. 3

Co-crystal structure of Bcl-xL and small-molecule inhibitor ABT-737. The interaction of alpha-helices (H) 1-9 from Bcl-xL (pink), in combination with ABT-737 (stick diagram) are highlighted in the presence of a chloride ion (green circle) and glycerol (unlabeled lower stick) in the left panel. Bcl-xL α-helices 2-5 (H2-H5) are highlighted in pink and yellow (middle panel) and in the right panel, are shown when viewed from above