Molecular pathways: targeting death receptors and smac mimetics.
Inhibitor of apoptosis (IAP) proteins are overexpressed in multiple human malignancies, an event that is associated with poor prognosis and treatment resistance. Therefore, IAP proteins represent relevant targets for therapeutic intervention. Second mitochondrial activator of caspases (Smac) is a mitochondrial protein that is released into the cytosol upon the induction of programmed cell death and promotes apoptosis by neutralizing IAP proteins. On the basis of this property, a variety of small-molecule inhibitors have been developed that mimic the binding domain of the native Smac protein to IAP proteins. Evaluation of these Smac mimetics in preclinical studies revealed that they particularly synergize together with agents that trigger the death receptor pathway of apoptosis. Such combinations might therefore be of special interest for being included in the ongoing evaluation of Smac mimetics in early clinical trials.
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany simone.fulda@kgu.de.
Simone
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Fulda
D000970:Antineoplastic Agents / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins; D040761:Biomimetic Materials / Q000737:chemistry*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry*; D011379:Prognosis; D053218:Receptors, Death Domain / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009842:Oligopeptides; D053218:Receptors, Death Domain; C532637:SMAC peptide