Design, synthesis and evaluation of monovalent Smac mimetics that bind to the BIR2 domain of the anti-apoptotic protein XIAP

作者：Gonzalez Lopez Marcos; Welsh Kate; Finlay Darren; Ardecky Robert J; Ganji Santhi Reddy; Su Ying; Yuan Hongbin; Teriete Peter; Mace Peter D; Riedl Stefan J; Vuori Kristiina; Reed John C; Cosford Nicholas D P^*

来源：Bioorganic & Medicinal Chemistry Letters, 2011, 21(14): 4332-4336.

DOI：10.1016/j.bmcl.2011.05.049

• Apoptosis
• XIAP
• Monovalent Smac mimietics
• Probe compounds

We report the systematic rational design and synthesis of new monovalent Smac mimetics that bind preferentially to the BIR2 domain of the anti-apoptotic protein XIAP. Characterization of compounds in vitro (including 9i; ML101) led to the determination of key structural requirements for BIR2 binding affinity. Compounds 9h and 9j sensitized TRAIL-resistant breast cancer cells to apoptotic cell death, highlighting the value of these probe compounds as tools to investigate the biology of XIAP.

• 出版日期2011-7-15