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Bivalent SMAC Mimetics for Treating Cancer by Antagonizing Inhibitor of Apoptosis Proteins
Author(s) -
Zhu Hongping,
Li Yi,
Liu Yue,
Han Bo
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900410
Subject(s) - xiap , inhibitor of apoptosis , bivalent (engine) , apoptosis , caspase , small molecule , activator (genetics) , programmed cell death , cancer cell , chemistry , cancer research , microbiology and biotechnology , biology , pharmacology , biochemistry , cancer , receptor , genetics , metal , organic chemistry
Inhibitors of apoptosis proteins (IAPs) inhibit caspase activity, allowing various cancers to reduce programmed cell death (apoptosis) and resist drug treatment. The second mitochondrial‐derived activator of caspases (SMAC) protein is an endogenous IAP antagonist, which can be considered as a potential anticancer therapy. Small‐molecule SMAC mimetics based on the Ala‐Val‐Pro‐Ile motif have been validated as potent IAP antagonists. In particular, most bivalent SMAC mimetics, which target both the baculovirus IAP repeat 2 (BIR2) and BIR3 domains in X‐linked IAP (XIAP), antagonize IAPs better than the corresponding monovalent mimetics. Here we focus on strategies for designing bivalent small‐molecule SMAC mimetics and progress in using them to antagonize IAPs. We also consider their clinical potential. Our discussion will hopefully help guide further study of these interesting mimetics.