Designed BH3 Peptides with High Affinity and Specificity for Targeting Mcl-1 in Cells

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• 作者：Glenna Wink Foight ; Jeremy A. Ryan ; Stefano V. Gull谩 ; Anthony Letai ; Amy E. Keating
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：September 19, 2014
• 年：2014
• 卷：9
• 期：9
• 页码：1962-1968
• 全文大小：333K
• ISSN：1554-8937

文摘

Mcl-1 is overexpressed in many cancers and can confer resistance to cell-death signaling in refractory disease. Molecules that specifically inhibit Mcl-1 hold potential for diagnosing and disrupting Mcl-1-dependent cell survival. We selected three peptides from a yeast-surface display library that showed moderate specificity and affinity for binding to Mcl-1 over Bfl-1, Bcl-x_L, Bcl-2, and Bcl-w. Specificity for Mcl-1 was improved by introducing threonine at peptide position 2e. The most specific peptide, MS1, bound Mcl-1 with 40-fold or greater specificity over four other human Bcl-2 paralogs. In BH3 profiling assays, MS1 caused depolarization in several human Mcl-1-dependent cell lines with EC₅₀ values of 鈭? 渭M, contrasted with EC₅₀ values of >100 渭M for Bcl-2-, Bcl-x_L-, or Bfl-1-dependent cell lines. MS1 is at least 30-fold more potent in this assay than the previously used Mcl-1 targeting reagent NoxaA BH3. These peptides can be used to detect Mcl-1 dependency in cells and provide leads for developing Mcl-1 targeting therapeutics.