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Pharmacol Ther. 2014 Oct;144(1):82-95. doi: 10.1016/j.pharmthera.2014.05.007. Epub 2014 May 16.

Small-molecule SMAC mimetics as new cancer therapeutics.

Author information

1
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.
2
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.
3
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.

Abstract

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.

KEYWORDS:

Apoptosis; Inhibitors; SMAC mimetics

PMID:
24841289
PMCID:
PMC4247261
DOI:
10.1016/j.pharmthera.2014.05.007
[Indexed for MEDLINE]
Free PMC Article

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