Lipophilic Isosteres of a 蟺鈥撓€ Stacking Interaction: New Inhibitors of the Bcl-2-Bak Protein鈥揚rotein Interaction

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• 作者：Naeem Yusuff ; Micha毛l Dor茅 ; Carol Joud ; Michael Visser ; Clayton Springer ; Xiaoling Xie ; Kara Herlihy ; Dale Porter ; B. Barry Tour茅
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：July 12, 2012
• 年：2012
• 卷：3
• 期：7
• 页码：579-583
• 全文大小：298K
• 年卷期：v.3,no.7(July 12, 2012)
• ISSN：1948-5875

文摘

The discovery of new Bcl-2 protein鈥損rotein interaction antagonists is described. We replaced the northern fragment of ABT737 (蟺鈥撓€ stacking interactions) with structurally simplified hydrophobic cage structures with much reduced conformational flexibility and rotational freedom. The binding mode of the compounds was elucidated by X-ray crystallography, and the compounds showed excellent oral bioavailability and clearance in rat PK studies.

Keywords:

Bcl-2 inhibitors; protein鈭抪rotein interaction; 蟺鈭捪€ stacking interactions; 蟺鈭捪€ stacking isosteres; bioisoteres; cancer therapeutics