期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 1, 页码 106-114出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm201072x
关键词
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资金
- Breast Cancer Research Foundation
- National Cancer Institute, NIH [R01CA109025, R01CA127551]
- Susan G. Koman Foundation
- Ascenta Therapeutics
- University of Michigan Cancer Center from the National Cancer Institute, NIH [P30CA046592]
Nonpeptidic, bivalent Smac mimetics designed based upon monovalent Smac mimetics with a diazabicyclic core structure bind to XIAP, cIAP1, and cIAP2 with low to subnanomolar affinities and are highly effective in antagonizing XIAP in cell-free functional assays. They efficiently induce the degradation of cIAP1 and cIAP2 in cancer cells at concentrations as low as 1 nM, activate caspase-3 and -8, and cleave PARP at 3-10 nM. The most potent compounds in the series have IC50 of 3-5 nM in inhibition of cell growth in both MDA-MB-231and SK-OV-3 cell lines and are promising lead compounds for the development of a new class of cancer therapy.
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