Discovery of Targeting Ligands for Breast Cancer Cells Using the One-Bead One-Compound Combinatorial Method

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• 作者：Nianhuan Yao ; Wenwu Xiao ; Xiaobing Wang ; Jan Marik ; See Hyoung Park ; Yoshikazu Takada ; Kit S. Lam
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：January 8, 2009
• 年：2009
• 卷：52
• 期：1
• 页码：126-133
• 全文大小：226K
• 年卷期：v.52,no.1(January 8, 2009)
• ISSN：1520-4804

文摘

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 α3 integrin was identified. Molecular interactions between α3 integrin and 1 were characterized by using a series of K562 cells transfected with various mutant α3 integrins. Using analytic flow cytometry, the binding affinity (K_d) of 1 to α3 integrin on MDA-MB-231 breast cancer cells was determined to be approximately 0.4 μM. 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 (IC₅₀ = 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.