The discovery of BCL-2 over twenty years ago revealed a new paradigm in cancer biology, namely that the development and persistence of cancer can be driven by molecular roadblocks along the natural pathway to cell death (Bakhshi et al., 1985; Cleary and Sklar, 1985; Tsujimoto et al., 1985). The subsequent identification of an expansive family of BCL-2 proteins provoked an intensive investigation of the interplay among these critical regulators of cell death. What emerged was a network of guardians and executioners, each participating in a molecular choreography that dictates cell fate (Danial and Korsmeyer, 2004). Ten years into the BCL-2 era, structural studies defined how an anti-apoptotic BCL-2 family protein binds and sequesters a pro-apoptotic protein by trapping its α-helical BH3 domain in a hydrophobic groove on the anti-apoptotic protein surface (Sattler et al., 1997). Because reactivating apoptosis in cancer is a desirable therapeutic goal, molecular targeting of BCL-2 family grooves has become a pharmacological quest. Small molecules and peptides that effectively target BCL-2 family members are beginning to demonstrate that clearing the roadblock to cell death may yield a medical breakthrough for cancer patients (Oltersdorf et al., 2005; Perez-Galan et al., 2007; Walensky et al., 2004).
MCL-1 functions at the mitochondrial outermembrane, where it neutralizes pro-apoptotic proteins such as NOXA, PUMA, BIM, and BAK. MCL-1 overexpression has been linked to the pathogenesis of multiple myeloma (Derenne et al., 2002; Zhang et al., 2002), chemoresistance in acute myeloid leukemia cells (Konopleva et al., 2006), and high tumor grade and poor prognosis in breast cancer (Ding et al., 2007). Indeed, sensitivity of cancer cells to ABT-737 inversely correlates with cellular levels of MCL-1 (van Delft et al., 2006); and siRNA-induced decreases in MCL-1 levels have been shown to resensitize cancer cells to ABT-737 (Konopleva et al., 2006). The development of specific inhibitors for the diversity of anti-apoptotic proteins remains a formidable challenge due to the diversity of their BH3-binding pockets. However, identification of such compounds would provide finely-tuned therapies to treat specific diseases and avoid potential toxicities of broader targeting. In addition, such compounds would serve as invaluable research tools to probe the biological functions of individual BCL-2 family protein interactions. Although there is a clear therapeutic rationale for targeting MCL-1, to date, a selective small molecule MCL-1 inhibitor has remained out of reach.
USPTO Backgrounds
USPTO Backgrounds