Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling

被引：36
作者：
Bayle, Elliott D. [1 ,2 ]
Svensson, Fredrik [1 ,2 ]
Atkinson, Benjamin N. [1 ]
Steadman, David [1 ]
Willis, Nicky J. [1 ]
Woodward, Hannah L. [1 ]
Whiting, Paul [1 ]
Vincent, Jean-Paul [2 ]
Fish, Paul, V [1 ,2 ]
机构：
[1] UCL, Alzheimers Res UK UCL Drug Discovery Inst, London WC1E 6BT, England
[2] Francis Crick Inst, London NW1 1AT, England
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 08期
基金：
英国工程与自然科学研究理事会; 英国惠康基金; 英国医学研究理事会;
关键词：
SMALL-MOLECULE INHIBITOR; STRUCTURAL BASIS; ENZYME NOTUM; BETA-CATENIN; CRYSTAL-STRUCTURE; PHASE-I; PROTEIN; PORCUPINE; RECEPTOR; PATHWAY;
D O I：
10.1021/acs.jmedchem.0c01974
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Regulation of the Wnt signaling pathway is critically important for a number of cellular processes in both development and adult mammalian biology. This Perspective will provide a summary of current and emerging therapeutic opportunities in modulating Wnt signaling, especially through inhibition of Notum carboxylesterase activity. Notum was recently shown to act as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group. Inhibition of Notum activity may represent a new approach to treat disease where aberrant Notum activity has been identified as the underlying cause. Reliable screening technologies are available to identify inhibitors of Notum, and structural studies are accelerating the discovery of new inhibitors. A selection of these hits have been optimized to give fit-for-purpose small molecule inhibitors of Notum. Three noteworthy examples are LP-922056 (26), ABC99 (27), and ARUK3001185 (28), which are complementary chemical tools for exploring the role of Notum in Wnt signaling.
引用
收藏
页码：4289 / 4311
页数：23
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