Dual-Specificity Phosphatase CDC25A/B Inhibitor Identified from a Focused Library with Nonelectrophilic Core Structure

Abstract

Focused libraries of enamine derivatives with a nonacidic, nonelectrophilic core structure were screened for inhibitors of dual-specificity protein phosphatases, and an o-hydroxybenzyl derivative RE44 (10d) was identified as a selective inhibitor of CDC25A/B. This inhibitor induced cell-cycle arrest of tsFT210 cells at the G2/M phase and inhibited dephosphorylation of the CDC25B substrate CDK1. Unlike most quinone-based inhibitors, 10d does not generate reactive oxygen species.

One Pot Synthesis of 3-Substituted-1-morpholino-1,2,4-triazole Mannich Bases and Their Activity Evaluation

“…要激酶, 对人体中的细胞分裂和基因表达起着重要的影 响, 是一种潜在的致癌基因而成为靶点, 因此筛选优良 的 Cdc25B 抑制剂可有效阻断癌细胞的增殖, 抑制癌症 [19] . 人工合成植物生长调节剂是与植物激素具有类似 生理和生物学效应的物质, 在农业生产上使用, 能有效 调节作物的生育过程, 成为改善品质、增强作物抗逆性 等重要措施 [20] , 设计研发新型植物生长调节剂, 调控植 …”

Mimicking/Extracting Structure and Functions of Natural Products: Synthetic Approaches that Address Unexplored Needs in Chemical Biology

“…We have synthesized approximately 160 compounds so far. Among the synthesized compounds, we identified three—VHR‐selective RE12 ( 12 ),[16] CDC25B selective RE44 ( 13 ),[17] and the original compound RE1 ( 4 )—as versatile inhibitors of VHR and CDC25A/B (Figure A).…”

“…It has characteristic biological functions on cell membranes, such as suppression of autophosphorylation of epidermal growth factor receptor (EGFR). It should be noted that this inhibitory activity is not exhibited by LacCer (17), which is structurally related, but does not have the sialic acid moiety at the nonreducing end. [21] These findings were mostly obtained by means of studies at the protein level using chemically synthesized glycan Chem.…”

Discovery of Cdc25A Lead Inhibitors with a Novel Chemotype by Virtual Screening: Application of Pharmacophore Modeling Based on a Training Set with a Limited Number of Unique Components

“…[14,15] In 2005, Brezak et al discovered quinone inhibitor BN82685w ith an IC 50 value of 0.25 mm. [20][21][22][23] Park et al identified five novel inhibitors from av irtual screening by using the docking method. [17] Although these quinones showedh igh selectivity to Cdc25 phosphatase, subsequent clinical tests failed.…”

“…[18] Thus, many studies have been focused on the discovery of novel inhibitors with different skeleton structures, [19] and virtuals creening wasw idely used in these studies for this specific purpose. [20][21][22][23] Park et al identified five novel inhibitors from av irtual screening by using the docking method. [23] The skeleton structures of these inhibitors are entirely different from those of the knownq uinones, which indicates an entire different pharmacophore feature for future virtual screenings.…”