Small-Molecule Inhibitors of Bcl-2 Family Proteins as Therapeutic Agents in Cancer
Ramzi Mohammad, Anshu Giri and Anton-Scott Goustin
Affiliation: Professor of Medicine,Division of Hematology and Oncology, Department of Internal Medicine/Karmanos Cancer Institute, Wayne State University School of Medicine, 724 HWCRC, 4100 John R Street, Detroit, MI 48201 USA.
This review focuses on the recent patents and use of small-molecule inhibitors (SMIs) of Bcl-2 family proteins as therapeutic agents against cancer. Bcl-2 members are crucial regulators of apoptotic cell death. Apoptosis is an evolutionarily conserved process of programmed cell death that plays an essential role in organism development and tissue homeostasis. Several mechanisms exist allowing cells to escape programmed cell death among them is the overexpression of the antiapoptotic proteins. Cancer cells are often found to overexpress many of these members such as Bcl-2, Bcl-XL, Mcl-1, Bcl-w and A1/Bfl1 and are usually resistant to a wide range of anti-cancer drugs and treatments. Many groups have been working to develop anti-cancer drugs that block the function of anti-apoptotic Bcl-2 members, thus favoring cell death. Methods include the downregulation of Bcl-2 expression or the use of peptides or small organic molecules to the Bcl-2 binding pocket, preventing its sequestration of proapoptotic proteins such as Bid and Bim. One of the most promising aspects of SMIs in treating cancer is that their targets and mechanisms of action are different from those of cytotoxic drugs and radiation. This makes it feasible to combine SMIs with other treatments, creating a synergistic therapy, without likely development of cross-resistance or increased toxicity. A broad-spectrum or “pan” SMI which targets multiple Bcl-2 family proteins is the goal.
Keywords: Bcl-2, Bcl-XL, Mcl-1, Bcl-w, A1/Bfl1, therapeutic gents, cancer, Bcl-2 expression
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