Apoptosis, or programmed cell death, is mis-regulated in 70% of human diseases and resistance to apoptosis is a hallmark of human cancer. Targeting key regulators of apoptosis with the goal to restore the normal apoptosis machinery is being pursued as a new approach for cancer treatment. Several classes of anti-death proteins play a key role in regulating apoptosis through heterodimerization with pro-death proteins. Blocking these protein-protein interactions using druglike small-molecules represents an attractive new therapeutic approach for cancer treatment. We will present our efforts in the design of highly potent and orally active small-molecule inhibitors to target these protein-protein interactions and illustrate the role that computational methods have played in these efforts. Furthermore, we will discuss the use of these highly potent and specific inhibitors as tools to learn new biology in vitro and in vivo and their therapeutic potential.
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