[Show abstract][Hide abstract] ABSTRACT: A series of acylpyrogallols were designed, synthesized, and evaluated as small-molecule inhibitors of antiapoptotic Bcl-2 proteins. The most potent compound 9 (TM-179) binds to Bcl-2 with an IC50 of 170 nM and to Mcl-1 with a Ki of 37 nM. Compound 9 potently inhibits cell growth and induces apoptosis in human breast and prostate cancer cell lines.
[Show abstract][Hide abstract] ABSTRACT: Structure-based strategy was employed to design flavonoid compounds to mimic the Bim BH3 peptide as a new class of inhibitors of the anti-apoptotic Bcl-2 proteins. The most potent compound, 4 (BI-33), binds to Bcl-2 and Mcl-1 with Ki values of 17 and 18 nM, respectively. Compound 4 inhibits cell growth in the MDA-MB-231 breast cancer cell line with an IC50 value of 110 nM and effectively induces apoptosis.
[Show abstract][Hide abstract] ABSTRACT: We report herein a new class of small-molecule inhibitors of antiapoptotic Bcl-2 proteins. The most potent compound, 7, binds to Bcl-2, Bcl-xL, and Mcl-1 proteins with Ki of 110, 638, and 150 nM, respectively. Compound 7 is highly effective in induction of cell death in breast cancer cells with high levels of Bcl-2, Bcl-xL, and Mcl-1 proteins and represents a promising lead compound for the design of new anticancer drugs. Apoptosis, or programmed cell death, is a critical cell process in normal development and homeostasis of multicellular organisms. Inappropriate regulation of apoptosis has been implicated in many human diseases, including cancer.1-3 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-2a family proteins are a class of central arbiters of apoptosis and consist of antiapoptotic members such as Bcl-2, Bcl-xL, and Mcl-1 and proapoptotic members such as Bim, Bid, Bak, and Bax.4-7 The antiapoptotic 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.4-7 Consequently, these antideath Bcl-2 proteins are considered to be promising molecular targets for the design of novel anticancer drugs.
[Show abstract][Hide abstract] ABSTRACT: A structure-based approach was employed to design a new class of small-molecule inhibitors of Bcl-2. The most potent compound 5 (TW-37) binds to Bcl-2 with a K(i) value of 290 nM and also to Bcl-xL and Mcl-1 with high affinities. Compound 5 potently inhibits cell growth in PC-3 prostate cancer cells with an IC(50) value of 200 nM and effectively induces apoptosis in a dose-dependent manner.