title: Novel dimeric Smac analogs as prospective anticancer agents.
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.
authors.affiliation: Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
authors.forename: Ewa D
authors.initials: ED
authors.lastname: Micewicz
authors.affiliation: Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
authors.forename: Hai T
authors.initials: HT
authors.lastname: Luong
authors.affiliation: Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
authors.forename: Chun-Ling
authors.initials: CL
authors.lastname: Jung
authors.affiliation: 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.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Waring
authors.affiliation: Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: McBride
authors.affiliation: Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA. Electronic address: pruchala@mednet.ucla.edu.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ruchala
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019281:Dimerization; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; C532637:SMAC peptide; D020169:Caspases
keywords: Apoptosis; New anticancer agents; Peptides; S-alkylation of peptides; Smac mimics