Design of novel BH3 mimetics for the treatment of chronic lymphocytic leukemia.

Impaired programmed cell death is an important factor in the pathogenesis of chronic lymphocytic leukemia (CLL) and in the development of resistance to chemoimmunotherapy. Hence, the reactivation of apoptotic processes is likely to be a pertinent strategy for circumventing this resistance. Proteins from the Bcl-2 family are critical elements in defective apoptosis. Some compounds induce the apoptosis of CLL cells ex vivo by downregulation of prosurvival members of this family (for example, Bcl-2 and Mcl-1), whereas others act by upregulation of proapoptotic Bcl-2 homology (BH) 3-only members (for example, Noxa and Bim). The concept of BH3 mimetics was prompted by the fact that BH3-only proteins are specific antagonistic ligands of prosurvival Bcl-2 family members. This led to the design of small molecules capable of inhibiting the activity of prosurvival Bcl-2 proteins and inducing apoptosis in leukemia cells in vitro and antileukemic effects in animal models. Several putative or actual BH3 mimetics are currently being trialed in the clinic. Two novel BH3 mimetics that can specifically bind to and antagonize Mcl-1 (a crucial antiapoptotic factor in CLL) have recently been discovered. The evaluation of this type of compound's clinical impact in CLL can now be considered.