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Structure-Based Design of 1,4-Dibenzoylpiperazines as ?-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction Inhibitors.

ABSTRACT: A small-molecule inhibitor with a 1,4-dibenzoylpiperazine scaffold was designed to match the critical binding elements in the ?-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction interface. Inhibitor optimization led to a potent inhibitor that can disrupt the ?-catenin/BCL9 interaction and exhibit 98-fold selectivity over the ?-catenin/cadherin interaction. The binding mode of new inhibitors was characterized by structure-activity relationships and site-directed mutagenesis studies. Cell-based studies demonstrated that this series of inhibitors can selectively suppress canonical Wnt signaling and inhibit growth of Wnt/?-catenin-dependent cancer cells.

SUBMITTER: Wisniewski JA

PROVIDER: S-EPMC4867476 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Structure-Based Design of 1,4-Dibenzoylpiperazines as β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction Inhibitors.

Wisniewski John A JA Yin Jinya J Teuscher Kevin B KB Zhang Min M Ji Haitao H

ACS medicinal chemistry letters 20160328 5

A small-molecule inhibitor with a 1,4-dibenzoylpiperazine scaffold was designed to match the critical binding elements in the β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction interface. Inhibitor optimization led to a potent inhibitor that can disrupt the β-catenin/BCL9 interaction and exhibit 98-fold selectivity over the β-catenin/cadherin interaction. The binding mode of new inhibitors was characterized by structure-activity relationships and site-directed mutagenesis studies. Ce ...[more]

PMID: 27190602

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