This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lu, J. Articles by Wang, S. Search for Related Content PubMed PubMed Citation Articles by Lu, J. Articles by Wang, S.

SM-164: A Novel, Bivalent Smac Mimetic That Induces Apoptosis and Tumor Regression by Concurrent Removal of the Blockade of cIAP-1/2 and XIAP

¹ University of Michigan Comprehensive Cancer Center; Departments of ² Internal Medicine, ³ Pharmacology, ⁴ Medicinal Chemistry, ⁵ Radiation Oncology, and ⁶ Biological Chemistry; and ⁷ Life Sciences Institute, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Shaomeng Wang, The University of Michigan, CCGC/3215, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0934. Phone: 734-615-0362; Fax: 734-647-9647; E-mail: shaomeng{at}umich.edu.

Key Words: Apoptosis • IAP proteins • Smac mimetics

Small-molecule Smac mimetics are being developed as a novel class of anticancer drugs. Recent studies have shown that Smac mimetics target cellular inhibitor of apoptosis protein (cIAP)-1/2 for degradation and induce tumor necrosis factor- (TNF)–dependent apoptosis in tumor cells. In this study, we have investigated the mechanism of action and therapeutic potential of two different types of novel Smac mimetics, monovalent SM-122 and bivalent SM-164. Our data showed that removal of cIAP-1/2 by Smac mimetics or small interfering RNA is not sufficient for robust TNF-dependent apoptosis induction, and X-linked inhibitor of apoptosis protein (XIAP) plays a critical role in inhibiting apoptosis induction. Although SM-164 is modestly more effective than SM-122 in induction of cIAP-1/2 degradation, SM-164 is 1,000 times more potent than SM-122 as an inducer of apoptosis in tumor cells, which is attributed to its much higher potency in binding to and antagonizing XIAP. SM-164 induces rapid cIAP-1 degradation and strong apoptosis in the MDA-MB-231 xenograft tumor tissues and achieves tumor regression, but has no toxicity in normal mouse tissues. Our study provides further insights into the mechanism of action for Smac mimetics and regulation of apoptosis by inhibitor of apoptosis proteins. Furthermore, our data provide evidence that SM-164 is a promising new anticancer drug for further evaluation and development. [Cancer Res 2008;68(22):9384–93]

This article has been cited by other articles:

				H. H. Cheung, D. J. Mahoney, E. C. LaCasse, and R. G. Korneluk Down-regulation of c-FLIP Enhances Death of Cancer Cells by Smac Mimetic Compound Cancer Res., October 1, 2009; 69(19): 7729 - 7738. [Abstract] [Full Text] [PDF]

				L. Bai, W. Chen, W. Chen, X. Wang, H. Tang, and Y. Lin IKK{beta}-mediated nuclear factor-{kappa}B activation attenuates smac mimetic-induced apoptosis in cancer cells Mol. Cancer Ther., June 1, 2009; 8(6): 1636 - 1645. [Abstract] [Full Text] [PDF]