Figure 1

Clinically relevant strategies for specific inhibition of Bcl-2 familyproteins. (a) Inhibition of the BH3-binding domain leads toapoptosis by decreased binding/sequestration of BH3-only proteins. Drugs such asABT-737 and ABT-263 inhibit the BH3 domains of Bcl-2 and Bcl-xL, while Maritoclaxinhibits Mcl-1. AT-101 and Obatoclax inhibit the BH3 domain of all Bcl-2 familymembers. While inhibition of the BH3-binding domains enhances apoptosis, thedomains of Mcl-1 that resist non-apoptotic processes (for example, senescence)remain unaffected. (b) Repression of Bcl-2 family protein production leadsto both apoptotic and non-apoptotic growth arrest by limiting the availability ofeach protein. Specific inhibitors have been designed, such as Genasense, anantisense oligonucleotide that targets BCL2 mRNA. On the other hand, thecompounds identified by Wei et al. preferentially affect MCL1.Future combinations of these therapies could hold the key for more clinicallyeffective treatments.