A Small Molecule ARTS Mimetics Degrade Both Major Anti-Apoptotic Proteins XIAP And Bcl-2 And Preferentially Kills Breast, Ovary and Kidney Cancer Cell Lines

ARTS (Sept4_i2) is a pro-apoptotic and tumor suppressor protein. ARTS promotes apoptosis by directly binding to both major anti-apoptotic proteins XIAP (X-Linked Inhibitor of apoptosis protein) and Bcl-2 (B-cell lymphoma 2), leading to their degradation by the Ubiquitin proteasome system (UPS). Studies in mice and human patient samples show that ARTS expression is lost in various types of cancers. In addition, many types of cancers escape cell death by overexpressing XIAP and Bcl-2. Thus, these two proteins have become major targets for developing anti-cancer therapeutics. Here we describe the identification of a small molecule, AM (ARTS Mimetic), that specifically binds to XIAP, but not cIAP1. AM initiates UPS-mediated degradation of both XIAP and Bcl-2, resulting in caspase activation and apoptosis. Significantly, treating Sept4/ARTS-null MEFs with AM successfully decreased the levels of XIAP and Bcl-2, suggesting that AM indeed mimics the main function of ARTS in promoting cell death. In addition, overexpression of XIAP rescued HeLa cells from AM-induced apoptosis. This confirms that AM indeed acts through binding and degrading XIAP. Collectively, our results describe the first ARTS mimetic small molecule that provides a novel approach for developing anti-cancer drugs that act by dual degradation of both XIAP and Bcl-2.