Bivalent SMAC Mimetics for Treating Cancer by Antagonizing Inhibitor of Apoptosis Proteins.
Hongping ZhuYi LiYue LiuBo HanPublished in: ChemMedChem (2019)
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.
Keyphrases
- small molecule
- oxidative stress
- cell death
- cell cycle arrest
- endoplasmic reticulum stress
- protein protein
- papillary thyroid
- immune response
- climate change
- cell therapy
- risk assessment
- bone marrow
- inflammatory response
- squamous cell
- young adults
- binding protein
- combination therapy
- human health
- replacement therapy
- smoking cessation
- childhood cancer