ja047438+_si_001.pdf (907.48 kB)
Structure-Based Design of Potent, Conformationally Constrained Smac Mimetics
journal contributionposted on 2004-12-29, 00:00 authored by Haiying Sun, Zaneta Nikolovska-Coleska, Chao-Yie Yang, Liang Xu, Meilan Liu, York Tomita, Hongguang Pan, Yoshiko Yoshioka, Krzysztof Krajewski, Peter P. Roller, Shaomeng Wang
A successful structure-based design and synthesis of a class of highly potent conformationally constrained Smac mimetics is described. The most potent compound has a Ki value of 25 nM binding to the XIAP BIR3 protein and is 23 times more potent than natural Smac peptides. These potent Smac mimetics can serve as powerful chemical and pharmacological tools to further elucidate the role of Smac and its cellular binding partners in apoptosis regulation and may be developed as a new class of anti-cancer drugs.