Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152).

@article{Flygare2012DiscoveryOA,
  title={Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152).},
  author={John A. Flygare and Maureen Beresini and Nageshwar Rao Budha and Helen H. Y. Chan and Iris T. Chan and Sravanthi Cheeti and Frederick Cohen and Kurt D Deshayes and Karl F. Doerner and Stephan Eckhardt and Linda O. Elliott and Bainian Feng and Matthew C. Franklin and Stacy Frankovitz Reisner and Lewis J. Gazzard and Jason S. Halladay and Sarah G. Hymowitz and Hank La and Patricia A. Lorusso and Brigitte Maurer and Lesley Murray and Emile G. Plise and Clifford L Quan and J Stephan and Shin G Young and Jeffrey Y K Tom and Vickie Tsui and Joanne Um and Eugene Varfolomeev and Domagoj Vu{\vc}i{\'c} and Andrew J Wagner and Heidi A Wallweber and Lan Wang and Joseph Alan Ware and Zhaoyang Wen and Harvey Wong and Jonathan M Wong and Melisa Shenshan Wong and Susan Sw Wong and Ron X Yu and Kerry Zobel and Wayne J Fairbrother},
  journal={Journal of medicinal chemistry},
  year={2012},
  volume={55 9},
  pages={
          4101-13
        }
}
A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K(i) values of 28, 14, 17, and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells… CONTINUE READING
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