Nevertheless, significant progress has been made in the last few years in the design of small-molecule inhibitors to target the Bcl-2 PPIs13C22 and a number of classes of potent small-molecule inhibitors, shown in Figure 1, have been reported

Nevertheless, significant progress has been made in the last few years in the design of small-molecule inhibitors to target the Bcl-2 PPIs13C22 and a number of classes of potent small-molecule inhibitors, shown in Figure 1, have been reported. programmed cell death, is a critical cell process in normal development and homeostasis of multicellular organisms. Inappropriate Pioglitazone hydrochloride regulation of apoptosis has been implicated in many human diseases, including cancer.1C3 Targeting critical apoptosis regulators is an attractive therapeutic approach for the development of new classes of therapies for the treatment of cancer and other human diseases.1 The Bcl-2 family proteins are a class of central arbiters of apoptosis and are comprised of anti-apoptotic members such as Bcl-2, Bcl-xL and Mcl-1 and pro-apoptotic members such as Bim, Bid, Bak and Bax.4C7 The anti-apoptotic proteins in the Bcl-2 family are overexpressed in many cancer cell lines and human cancer tissues. This overexpression protects cancer cells from the induction of apoptosis by current anticancer therapies and plays a role in the failure of conventional anticancer drugs.4C7 Consequently, these anti-death Bcl-2 proteins are considered to be Pioglitazone hydrochloride promising molecular targets for the design of novel anticancer drugs. Although the precise mechanism Rabbit Polyclonal to AKAP4 by which Bcl-2 proteins regulate apoptosis in cells is still under intense Pioglitazone hydrochloride investigation,8 it is very clear that these anti-apoptotic Bcl-2 proteins effectively inhibit apoptosis, at least in part, by directly binding to pro-apoptotic Bcl-2 proteins such as Bim, Bid, Bak and Bax and blocking their pro-apoptotic activity. Experimentally determined three- dimensional structures of Bcl-2, Bcl-xL and Mcl-1 by either NMR or x-ray crystallography showed that the BH1 (Bcl-2 homology domain 1), BH2 and BH3 domains in these proteins form a well-defined, hydrophobic surface binding groove, known as the BH3 binding groove, into which Bad, Bid and Bim bind.9C12 Hence, small-molecules that are designed to target the BH3 binding groove in these anti-apoptotic Bcl-2 proteins are predicted to promote apoptosis in cancer cells by antagonizing their anti-apoptotic function. Design of non-peptide, cell-permeable, small-molecule inhibitors that bind to the BH3 binding groove in these anti-death Bcl-2 proteins is being intensely pursued as a new anticancer therapeutic strategy.13C22 Design of non-peptidic, small-molecule inhibitors to target protein-protein interactions (PPIs) is considered one of the most challenge tasks in modern drug discovery and medicinal chemistry. Nevertheless, significant progress has been made in the last few years in the design of small-molecule inhibitors to target the Bcl-2 PPIs13C22 and a number of classes of potent small-molecule inhibitors, shown in Figure 1, have been reported. Among them, compound 1 binds to Bcl-2, Bcl-xL and Bcl-w proteins with a very high affinity but does not bind to Mcl-1.18 Compound 2, a natural product isolated from cotton seeds, concurrently targets Bcl-2, Bcl-xL and Mcl-1 proteins with similar affinities,21 and is currently in clinical trials as an orally administered agent for the treatment of multiple forms of human cancer.22 Using a structure-based strategy, we have recently reported the design of compound 3 as a new class of potent, cell-permeable small-molecule inhibitor of Bcl-2, Bcl-xL and Mcl-1 proteins.21 Open in a separate window Figure 1 Representative small-molecule inhibitors of Bcl-2 proteins. Although Bcl-2 and Bcl-xL proteins have been the primary focus for the design of small-molecule inhibitors to target these proteins,13C22 recent studies have demonstrated that the Mcl-1 protein plays a crucial role in protecting cancer cells from induction of apoptosis by a variety of anticancer agents. Compound 1 had potent activity only in cancer cells with low levels of Mcl-1 protein but a much weaker activity in cancer cells with high levels of Mcl-1.23 Knocking down Mcl-1 using siRNA in cancer cells greatly sensitizes the activity of 1 1. Hence, small-molecule inhibitors that target not only Bcl-2 and Bcl-xL but also Mcl-1 could be highly effective in induction of cell death in cancer cells with high levels of these proteins. Herein, we report the structure-based design, synthesis, initial evaluations of pyrogallol based compounds as novel small-molecule inhibitors of Bcl-2, Bcl-xL and Mcl-1. In our previous study,21 compound 4 was designed as an initial lead starting from compound 2 (Figure 2). In our fluorescence polarization (FP)-based binding assay, 4 binds to Bcl-2 with a Ki value of 31.9 M (Figure 3). Analysis of its binding model to Bcl-2 (Figure 4 and Supporting Information) showed that two of the hydroxyl groups in its phenyl ring form hydrogen bonds with R146 and N143 in Bcl-2, mimicking the key.