In one hypothesis of regulation of cell death by Bcl-2 family proteins, the BH3-only proteins are further categorized as either “activator” (e.g., Bim and Bid) or “sensitizer” (e.g., Bad, Bik, Noxa, Hrk, Bmf, and Puma) proteins depending on their regulatory function. The exact mechanism by which the Bcl-2 family proteins regulate cell death is still not entirely known and understanding this mechanism is an active area of research in the science community. Bim, Bid, Bad, Bik, Noxa, Hrk, Bmf, and Puma are examples of this third subfamily of proteins. Finally, the third subgroup is composed of proteins containing only the BH3 domain and members of this subgroup are usually referred to as “BH3-only proteins.” Their biological effect on the cell is pro-apoptotic. The two main representative proteins of this second subgroup are Bax and Bak. Proteins belonging to the second subgroup contain the three homology domain BH1, BH2 and BH3, and have a pro-apopiotic effect. Proteins such as, for example, Bcl-2, Bcl-w, Bcl-xL, Mcl-1 and Bfl-1/A1 are members of this first subgroup. Their general effect is anti-apoptotic, that is to preserve a cell from starting a cell death process.
The first subgroup contains proteins having all 4 homology domains, BH1, BH2, BH3 and BH4. The Bcl-2 family of proteins can be further classified into three subfamilies depending on how many of the homology domains each protein contains and on its biological activity (i.e., whether it has pro- or anti-apoptotic function). The structural homology domains BH1, BH2, BH3 and BH4 are characteristic of this family of proteins. Several apoptotic pathways have been uncovered, and one of the most important involves the Bcl-2 family of proteins, which are key regulators of the mitochondrial (also called “intrinsic”) pathway of apoptosis. Later in life, cell death is a default mechanism by which potentially dangerous cells (e.g., cells, carrying cancerous defects) are removed. In mammals in particular, it has been shown to regulate early embryonic development.
BACKGROUND OF THE INVENTIONĪpoptosis is recognized as an essential biological process for tissue homeostasis of all living species. This invention pertains to compounds which inhibit the activity of Bcl-xL anti-apoptotic proteins, compositions containing the compounds, and methods of treating diseases during which anti-apoptotic Bcl-xL proteins are expressed. 14, 2011, each of which are incorporated by reference in its entirety. This application is a continuation of U.S.
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