Novel dimeric Smac analogs as prospective anticancer agents

Ewa D Micewicz; Hai T Luong; Chun-Ling Jung; Alan J Waring; William H McBride; Piotr Ruchala

doi:10.1016/j.bmcl.2014.02.024

Novel dimeric Smac analogs as prospective anticancer agents

Bioorg Med Chem Lett. 2014 Mar 15;24(6):1452-7. doi: 10.1016/j.bmcl.2014.02.024. Epub 2014 Feb 18.

Authors

Ewa D Micewicz¹, Hai T Luong², Chun-Ling Jung², Alan J Waring³, William H McBride¹, Piotr Ruchala⁴

Affiliations

¹ Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
² Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
³ Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90502, USA; Department of Physiology and Biophysics, University of California Irvine, 1001 Health Sciences Road, Irvine, CA 92697, USA.
⁴ Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA. Electronic address: [email protected].

PMID: 24582479
DOI: 10.1016/j.bmcl.2014.02.024

Abstract

A small library of monovalent Smac mimics with general structure NMeAla-Tle-(4R)-4-Benzyl-Pro-Xaa-cysteamide, was synthesized (Xaa=hydrophobic residue). The library was screened in vitro against human breast cancer cell lines MCF-7 and MDA-MB-231, and two most active compounds oligomerized via S-alkylation giving bivalent and trivalent derivatives. The most active bivalent analogue SMAC17-2X was tested in vivo and in physiological conditions (mouse model) it exerted a potent anticancer effect resulting in ∼23.4days of tumor growth delay at 7.5mg/kg dose. Collectively, our findings suggest that bivalent Smac analogs obtained via S-alkylation protocol may be a suitable platform for the development of new anticancer therapeutics.

Keywords: Apoptosis; New anticancer agents; Peptides; S-alkylation of peptides; Smac mimics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Breast Neoplasms / drug therapy
Caspases / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Dimerization
Female
Humans
MCF-7 Cells
Mice
Oligopeptides / chemistry*
Oligopeptides / pharmacology*
Oligopeptides / therapeutic use

Substances

Antineoplastic Agents
Oligopeptides
SMAC peptide
Caspases