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Lipophilic Isosteres of a pi-pi Stacking Interaction: Design of New Inhibitors of the Bcl-2-Bak Protein-Protein Interaction.

Yusuff, Naeem and Dore, Michael and Joud, Carol and Visser, Michael and Springer, Clayton and Xie, Xiaoling and Herlihy, Kara and Porter, Dale and Toure, Bakary-Barry (2012) Lipophilic Isosteres of a pi-pi Stacking Interaction: Design of New Inhibitors of the Bcl-2-Bak Protein-Protein Interaction. ACS medicinal chemistry letters, 3 (7). pp. 579-583. ISSN 1948-5875

Abstract

The discovery of new Bcl-2 protein-protein interaction antagonists is described. We replaced the northern fragment of ABT737 (π- π 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.

Item Type: Article
Keywords: Bcl-2 inhibitors, protein-protein interaction, π- π stacking interactions, π- π stacking isosteres, bioisoteres, cancer therapeutics.
Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6701

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