Discovery of targeting ligands for breast cancer cells using the one-bead one-compound combinatorial method.

Abstract

Four "one-bead one-compound" (OBOC) combinatorial libraries were designed, synthesized, and screened against MDA-MB-231 breast cancer cells. A novel cyclic peptide 1 (LXY1) with high binding specificity to alpha3 integrin was identified. Molecular interactions between alpha3 integrin and 1 were characterized by using a series of K562 cells transfected with various mutant alpha3 integrins. Using analytic flow cytometry, the binding affinity (K(d)) of 1 to alpha3 integrin on MDA-MB-231 breast cancer cells was determined to be approximately 0.4 microM. Based on the established structure-activity relationship (SAR) study, two highly focused cyclic peptide libraries were further designed, synthesized, and screened against MDA-MB-231 breast cancer cells under stringent conditions. A novel cyclic peptide 2 (LXY3) with a high binding affinity (IC(50) = 57 nM) was identified. Moreover, the targeting efficiency and specificity of 2 to the breast adenocarcinoma tumors in mouse xenografts were further confirmed by in vivo and ex vivo near-infrared fluorescence optical imaging.

• Authors: Nianhuan Yao, Wenwu Xiao, Xiaobing Wang, Jan Marik, See Hyoung Park, Yoshikazu Takada, Kit S Lam
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 1 Pg. 126-33 (Jan 08 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19055415 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Integrin alpha3
• Ligands
• Peptides

Topics

• Animals
• Biomimetic Materials (chemical synthesis, chemistry, metabolism)
• Biotinylation
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Combinatorial Chemistry Techniques
• Databases, Protein
• Drug Design
• Female
• Humans
• Integrin alpha3 (metabolism)
• Ligands
• Magnetic Resonance Spectroscopy
• Mice
• Mice, Nude
• Molecular Structure
• Peptides (chemical synthesis, chemistry, metabolism)
• Structure-Activity Relationship
• Substrate Specificity
• Xenograft Model Antitumor Assays