Rational Design of Helix-Mimicking Small Molecules for Inhibiting BCL-2 Proteins in Prostate Cancer

摘要

Cell death occurs for many reasons including physiological and pathological factors and plays a crucial role in the process of development, aging and diseases. The fate of a cell depends on an appropriate response to various environmental or intracellular stress stimuli and the mechanism of cell death can be broadly classified into two types, apoptotic and non-apoptotic. Apoptosis is largely regulated by protein-protein interactions between Bcl-2 family proteins that comprise of three groups. Anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, Al) are responsible for cell survival and have four conserved domains (BH1-BH4). Pro-apoptotic members induce cell death and are further classified to multi-domain proteins bearing BH1-BH3 (e.g., Bak, Bax) and BH3-only proteins (e.g., Bim, Bik, Bid, Puma, Noxa). The process of apoptosis is initiated by BH3-only proteins either activating multi-domain pro-apoptotic proteins or inhibiting anti-apoptotic members (direct or indirect activation model, respectively), resulting in release of cytochrome c through mitochondrial outer membrane permeability [1]. This event in turn begins caspase cascade that ultimately leads to cell death. Thus, small molecules that inhibit anti-apoptotic Bcl-2 proteins or activate pro-apoptotic ones would be of high interest in treating cancers.