Structure-based design of 1,4-dibenzoylpiperazines to disrupt BCL9 interactions and downregulate Wnt signaling.

While the Wnt/β-catenin signaling pathway is necessary for many normal pathways (embryonic development, stem cell maintenance, etc.), hyperactivation of Wnt signaling can cause a range of pathologies including cancer and excessive fibrosis. Although other attempts to inhibit this pathway have found mild success (e.g. carnosic acid), more effective inhibitors are required to advance to clinical testing and offer a new option for lymphoma patients.

Researchers at the University of Utah have designed and synthesized a series of selective small-molecule inhibitors with the 4-substituted benzoylpiperazine-1-substituted carbonyl scaffold to inhibit the beta-catenin/B-cell lymphoma 9 (BCL9) complex. Cell-based studies demonstrated that this series of compounds can effectively disrupt the β-catenin/BCL9 interaction and selectively downregulate Wnt signaling.

Lead Identified

• The designed inhibitors exhibit up to a 98-fold selectivity over the β-catenin/cadherin interaction
• The piperazine moiety in some of the molecules can be functionalized to allow additional optimizations

Wisniewski J, et al. (2016). Structure-Based Design of 1,4-Dibenzoylpiperazines as β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction Inhibitors. ACS Med Chem Lett, 7(5): 508-13. doi: 10.1021/acsmedchemlett.5b00284.

Publication Number: 2021/0171502
Patent Title: Methods and composition of 4-substituted benzoylpiperazine-1-substituted carbonyls as beta-catenin/B-cell lymphoma 9 inhibitors
Jurisdiction/Country: United States
Application Type: Non-Provisional

Jason Young
(801) 587-0519
jason.r.young@utah.edu