Members of the Bcl-2 family of proteins are crucial regulators of programmed cell death or apoptosis. This family of proteins now includes both anti-apoptotic molecules such as Bcl-2 and Bcl-XL, and pro-apoptotic molecules such as Bax, Bak, Bid, and Bad. The majority of human cancers are found to have overexpression of Bcl-2, Bcl-XL, or both. Bcl-2 and Bcl-XL may play a critical role in cancer progression. Cancers with high levels of Bcl-2 or Bcl-XL or both proteins are resistant to a wide spectrum of chemotherapeutic agents and radiation therapy. Bcl-2 and Bcl-XL have become attractive targets for designing new anticancer drugs. Small-molecule inhibitors that are capable of inhibiting the activity of Bcl-2 and Bcl-XL may have great therapeutic potential as an entirely new class of anticancer drugs for treating many forms of cancers in which Bcl-2 and/or Bcl-XL proteins are overexpressed and for which traditional therapies are ineffective. Design of small-molecule inhibitors of Bcl-2 and Bcl-XL is a very new and exciting area for current anticancer drug design and development. In this article we will provide a brief review on the strategy and recent progress in designing small-molecule antagonists targeting Bcl-2 and Bcl-XL.
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