Small-molecule inhibitors of Bcl-2 protein

Approaches to drug discovery are varied and range from high-resolution NMR solution structure of targeted molecules to rational design. This review is focused on the use of small-molecule inhibitors of Bcl-2 as therapeutic agents. Members of the Bcl-2 family of proteins are crucial regulators of apoptotic cell death. Human cancers have been found to overexpress Bcl-2 and Bcl-XL. Cells with high levels of these antiapoptotic molecules are usually resistant to a wide spectrum of chemotherapeutic drugs. Targeting the Bcl-2 family of proteins with small-molecules inhibitors has therefore become an attractive potential therapy for a variety of cancers. The role Bcl-2 in sabotaging the success of cytotoxic agents suggest that novel treatments should be devised to target Bcl-2-overexpressing tumor cells and induce apoptotis directly. In this article, we will provide a review of potential small-molecule inhibitors as anticancer agents. The deregulated overexpression of Bcl-2 and Bcl-XL is directly related to cancer cell survival and resistance to chemotherapeutic drugs, making antagonists or inhibitors of these proteins very promising candidates for use in cancer therapy.