文献类型：期刊文献

英文题名：Structure-Based Optimization of Small-Molecule Inhibitors for the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction

作者：Zhang, Min[1,2,3];Wang, Zhen[1,2,3];Zhang, Yongqiang[1,2,3,4];Guo, Wenxing[1,2,3,5];Ji, Haitao[1,2,3]

机构：[1]H Lee Moffitt Canc Ctr & Res Inst, Drug Discovery Dept, Tampa, FL 33612 USA;[2]Univ S Florida, Dept Oncol Sci, Tampa, FL 33620 USA;[3]Univ S Florida, Dept Chem, Tampa, FL 33620 USA;[4]East China Univ Sci & Technol, State Key Lab Bioengn Reactor, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[5]Univ Utah, Dept Chem, Grad Program, Salt Lake City, UT 84112 USA

年份：2018

卷号：61

期号：7

起止页码：2989

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000430256600024)】；

基金：This work was supported by the Department of Defense CDMRP BCRP breakthrough award W81XWH-14-1-0083. We thank John A. Wisniewski, Daniel Powell, and Jinya Yin for the initial synthesis of some compounds. The H. Lee Moffitt Cancer Center & Research Institute is an NCI-designated Comprehensive Cancer Center, supported under NIH grant P30-CA76292.

语种：英文

摘要：Structure-based optimization was conducted to improve the potency, selectivity, and cell-based activities of beta-catenin/B-cell lymphoma 9 (BCL9) inhibitors based on the 4'-fluoro-N-phenyl-[1,1'-biphenyl]-3-carboxamide scaffold, which was designed to mimic the side chains of the hydrophobic a-helical hot spots at positions i, i + 3, and i + 7. Compound 29 was found to disrupt the beta-catenin/BCL9 protein-protein interaction (PPI) with a K-i of 0.47 mu M and >1900-fold selectivity for beta-catenin/BCL9 over beta-catenin/E-cadherin PPIs. The proposed binding mode of new inhibitors was consistent with the results of site-directed mutagenesis and structure-activity relationship studies. Cell-based studies indicated that 29 disrupted the beta-catenin/BCL9 interaction without affecting the beta-catenin/E-cadherin interaction, selectively suppressed transactivation of Wnt/beta-catenin signaling, downregulated expression of Wnt target genes, and inhibited viability of Wnt/beta-catenin-dependent cancer cells in dose-dependent manners. A comparison of the biochemical and cell-based assay results offered the directions for future inhibitor optimization.