通过一种新机制恢复癌细胞系中E-钙黏蛋白表达的小分子的发现与特性研究

Discovery and characterization of a small molecule that restores E-cadherin expression in cancer cell lines via a new mechanism

作者信息

Stoops Sydney L., Waterson Alex G., An Hanbing, Deane Natasha, Daniels J. Scott, Morrison Ryan, Engers Julie L., Beauchamp Daniel, Lindsley Craig W.

机构信息

Vanderbilt University Medical Center

Vanderbilt Specialized Chemistry Center- Vanderbilt University Medical Center

PMID:26913352

Abstract

Herein we report the discovery and structure activity relationship (SAR) of a novel, small molecule (ML327) that restores E-cadherin expression through regulation of E-cadherin transcription. ML327 was discovered via an iterative parallel synthesis optimization of a first generation ligand, but ML327 is >50-fold more effective in restoring E-cadherin expression. This transcriptional regulator (CID 60167648, ML327) displays an In-Cell Western EC value of 1.0 μM and is inactive (>30 μM) against all know epigenetic targets (HDACs, MMPs, sirtuins, etc.) that increase E-cadherin expression, and clean in a Ricerca ancillary pharmacology panel. ML327 possesses favorable physiochemical properties, an excellent dystrophia myotonica protein kinase (DMPK) profile. Thus, ML327 is valuable probe for studying E-cadherin expression in tumor cell lines via a novel mechanism of regulating E-cadherin transcription.

摘要

在此，我们报告了一种新型小分子（ML327）的发现及其结构活性关系（SAR），该小分子通过调节E-钙黏蛋白转录来恢复E-钙黏蛋白的表达。ML327是通过对第一代配体进行迭代平行合成优化而发现的，但ML327在恢复E-钙黏蛋白表达方面的效果要高出50倍以上。这种转录调节因子（CID 60167648，ML327）在细胞内western实验中的EC值为1.0 μM，对所有已知的能增加E-钙黏蛋白表达的表观遗传靶点（组蛋白去乙酰化酶、基质金属蛋白酶、沉默调节蛋白等）均无活性（>30 μM），并且在Ricerca辅助药理学筛选中表现良好。ML327具有良好的理化性质，肌强直性营养不良蛋白激酶（DMPK）特征优良。因此，ML327是通过调节E-钙黏蛋白转录的新机制研究肿瘤细胞系中E-钙黏蛋白表达的有价值的探针。