Activation of the Proapoptotic Bcl-2 Protein Bax by a Small Molecule Induces Tumor Cell Apoptosis

The proapoptotic Bcl-2 protein Bax by itself is sufficient to initiate apoptosis in almost all apoptotic paradigms. Thus, com-pounds that can facilitate disruptive Bax insertion into mitochondrial membranes have potential as cancer therapeutics. In our study, we have identified small-molecule compounds predicted to associate with the Bax hydrophobic groove by a virtual-screen approach. Among these, one lead compound (compound 106) promotes Bax-dependent but not Bak-dependent apoptosis. Im-portantly, this compound alters Bax protein stability in vitro and promotes the insertion of Bax into mitochondria, leading to Bax-dependent permeabilization of the mitochondrial outer membrane. Furthermore, as a single agent, compound 106 inhibits the growth of transplanted tumors, probably by inducing apoptosis in tumors. Our study has revealed a compound that activates Bax and induces Bax-dependent apoptosis, which may lead to the development of new therapeutic agents for cancer. Resistance to apoptosis is a hallmark of most, perhaps all, typesof human cancer (1–3). Bcl-2 proteins are the major regula-tors of apoptotic signaling pathways, and each Bcl-2 protein mem-ber has at least one Bcl-2 homology (BH) domain (4–6). Bcl-2 proteins can be classified into antiapoptotic and proapoptotic groups. There are also two classes of proapoptotic Bcl-2 proteins: multiple-BH-domain and BH3-only proteins (5). Antiapoptotic Bcl-2 proteins are believed to protect against disintegration of th