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Review
. 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

Longchuan Bai  1 , David C Smith  2 , Shaomeng Wang  3
Affiliations
Review

Small-molecule SMAC mimetics as new cancer therapeutics

Longchuan Bai et al. Pharmacol Ther. 2014 Oct.

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.

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Conflict of interest statement

Conflict of Interest Statement: Ascenta and Debiopharm have licensed AT-406 for clinical development from the University of Michigan. S. Wang is an inventor of AT-406 and receives research support from Debiopharm and owns stock in Ascenta. D.C. Smith has received research support from Ascenta and Debiopharm.

Figures

Figure 1
Figure 1
Functional domains of mammalian inhibitor of apoptosis proteins (IAPs). BIR: baculoviral IAP repeat domain; UBA: Ubiquitin-associated domain; CARD: caspase recruitment domain; RING: Really interesting new gene finger domain.
Figure 2
Figure 2
IAP proteins play prominent roles in NF-κB signaling and cell death pathways. See the text for details.
Figure 3
Figure 3
(A) Crystal structure of the dimeric Smac protein in complex with two XIAP BIR3 proteins (PDBID: 1G73). The AVPI motifs are shown in ball models. (B) Detailed interactions between the AVPI binding motif and XIAP BIR3 residues. Oxygen and nitrogen atoms are colored in red and blue colors. Hydrogen bonds are depicted in dash lines. Electrostatic surfaces of XIAP BIR3 are shown where the red, grey and blue colors denote negative, neutral and positive charged regions. The figures are prepared using the PyMOL and APBS programs.
Figure 4
Figure 4
Chemical structures of representative small-molecule SMAC mimetics.
See this image and copyright information in PMC

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