Wang Zhen, Zhang Min, Thompson Harriet M, Ji Haitao
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612-9497, United States.
Department of Chemistry, University of South Florida, Tampa, Florida 33620-9497, United States.
ACS Med Chem Lett. 2022 Apr 25;13(5):865-870. doi: 10.1021/acsmedchemlett.2c00068. eCollection 2022 May 12.
A series of 1-(3-(2-amino-2-oxoethoxy)phenyl)piperidine-3-carboxamide derivatives was reported as new small-molecule β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) inhibitors. Compounds - were discovered to inhibit the β-catenin/BCL9 PPI with = 0.85-2.7 μM. The effects of on the β-catenin/BCL9 PPI in cellular context were demonstrated by β-catenin/BCL9 pull-down inhibition and dose-dependent suppression of Wnt/β-catenin signal transactivation. Notably, compound is more potent than , a previously reported analogue, in modulating transcription and expression of β-catenin target genes and suppressing survival of β-catenin-dependent cancer cells. The cellular on-target efficacy of was demonstrated by β-catenin rescue experiments. Compound represents a promising starting point for further optimization of β-catenin/BCL9 PPI inhibitors.
据报道，一系列1-(3-(2-氨基-2-氧代乙氧基)phenyl)哌啶-3-甲酰胺衍生物是新型小分子β-连环蛋白/B细胞淋巴瘤9（BCL9）蛋白-蛋白相互作用（PPI）抑制剂。发现化合物抑制β-连环蛋白/BCL9 PPI的IC₅₀为0.85 - 2.7 μM。通过β-连环蛋白/BCL9下拉抑制和Wnt/β-连环蛋白信号转激活的剂量依赖性抑制，证明了其在细胞环境中对β-连环蛋白/BCL9 PPI的作用。值得注意的是，在调节β-连环蛋白靶基因的转录和表达以及抑制β-连环蛋白依赖性癌细胞的存活方面，化合物比先前报道的类似物更有效。通过β-连环蛋白拯救实验证明了化合物的细胞靶向疗效。化合物为进一步优化β-连环蛋白/BCL9 PPI抑制剂提供了一个有前景的起点。
