Small-molecule SMAC mimetics as new cancer therapeutics.
Apoptosis is a tightly regulated cellular process and faulty regulation of apoptosis is a hallmark of human cancers. Targeting key apoptosis regulators with the goal to restore apoptosis in tumor cells has been pursued as a new cancer therapeutic strategy. XIAP, cIAP1, and cIAP2, members of inhibitor of apoptosis (IAP) proteins, are critical regulators of cell death and survival and are attractive targets for new cancer therapy. The SMAC/DIABLO protein is an endogenous antagonist of XIAP, cIAP1, and cIAP2. In the last decade, intense research efforts have resulted in the design and development of several small-molecule SMAC mimetics now in clinical trials for cancer treatment. In this review, we will discuss the roles of XIAP, cIAP1, and cIAP2 in regulation of cell death and survival, and the design and development of small-molecule SMAC mimetics as novel cancer treatments.
Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
Longchuan
L
Bai
Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address: dcsmith@med.umich.edu.
David C
DC
Smith
Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address: shaomeng@umich.edu.
Shaomeng
S
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002470:Cell Survival / Q000502:physiology; D015195:Drug Design; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
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; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C494833:BIRC2 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases
Apoptosis; Inhibitors; SMAC mimetics