Small-molecule SMAC mimetics as new cancer therapeutics

Longchuan Bai; David C Smith; Shaomeng Wang

doi:10.1016/j.pharmthera.2014.05.007

Small-molecule SMAC mimetics as new cancer therapeutics

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

Authors

Longchuan Bai¹, David C Smith², Shaomeng Wang³

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Review

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Apoptosis / physiology
Apoptosis Regulatory Proteins
Baculoviral IAP Repeat-Containing 3 Protein
Cell Survival / physiology
Drug Design*
Humans
Inhibitor of Apoptosis Proteins / metabolism
Intracellular Signaling Peptides and Proteins / metabolism
Mitochondrial Proteins / metabolism
Neoplasms / drug therapy*
Neoplasms / pathology
Ubiquitin-Protein Ligases
X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

Antineoplastic Agents
Apoptosis Regulatory Proteins
DIABLO protein, human
Inhibitor of Apoptosis Proteins
Intracellular Signaling Peptides and Proteins
Mitochondrial Proteins
X-Linked Inhibitor of Apoptosis Protein
XIAP protein, human
BIRC2 protein, human
BIRC3 protein, human
Baculoviral IAP Repeat-Containing 3 Protein
Ubiquitin-Protein Ligases

Abstract

Publication types

MeSH terms

Substances

Grants and funding