Lipid-conjugated Smac analogues

Ewa D Micewicz; Josephine A Ratikan; Alan J Waring; Julian P Whitelegge; William H McBride; Piotr Ruchala

doi:10.1016/j.bmcl.2015.09.017

Lipid-conjugated Smac analogues

Bioorg Med Chem Lett. 2015 Oct 15;25(20):4419-27. doi: 10.1016/j.bmcl.2015.09.017. Epub 2015 Sep 8.

Authors

Ewa D Micewicz¹, Josephine A Ratikan¹, Alan J Waring², Julian P Whitelegge³, 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, 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.
³ Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA; The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, Los Angeles, CA 90024, USA.
⁴ Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA; The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, Los Angeles, CA 90024, USA. Electronic address: [email protected].

Abstract

A small library of monovalent and bivalent Smac mimics was synthesized based on 2 types of monomers, with general structure NMeAla-Xaa-Pro-BHA (Xaa=Cys or Lys). Position 2 of the compounds was utilized to dimerize both types of monomers employing various bis-reactive linkers, as well as to modify selected compounds with lipids. The resulting library was screened in vitro against metastatic human breast cancer cell line MDA-MB-231, and the two most active compounds selected for in vivo studies. The most active lipid-conjugated analogue M11, showed in vivo activity while administered both subcutaneously and orally. Collectively, our findings suggest that lipidation may be a viable approach in the development of new Smac-based therapeutic leads.

Keywords: Anticancer agents; Apoptosis; Lipids-conjugated peptides; S-Alkylation of peptides; Smac mimics.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Apoptosis Regulatory Proteins
Cell Line, Tumor
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Intracellular Signaling Peptides and Proteins / chemistry*
Intracellular Signaling Peptides and Proteins / metabolism
Lipids / chemistry*
Mice
Mitochondrial Proteins / chemistry*
Mitochondrial Proteins / metabolism
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Apoptosis Regulatory Proteins
DIABLO protein, human
Intracellular Signaling Peptides and Proteins
Lipids
Mitochondrial Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding