Identification of 2-aminopyrimidine derivatives as inhibitors of the canonical Wnt signaling pathway
Identification of 2-aminopyrimidine derivatives as inhibitors of the canonical Wnt signaling pathway
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DOI：
10.1016/j.bmc.2015.07.015
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发表时间：
2015-09-01
影响因子：
3.5
通讯作者：
Varrone, Maurizio
中科院分区：
文献类型：
--
作者：
Del Bello, Fabio;Farande, Aniket;Varrone, Maurizio
经典的Wnt信号通路在胚胎发育和成体发育中起着重要作用。因此，该途径的失调与广泛的病理状况有关。在一个旨在鉴定经典Wnt途径的小分子抑制剂的项目中，我们鉴定了一系列2-氨基嘧啶衍生物，其特异性抑制该途径，具有最小的细胞毒性或没有细胞毒性的迹象。命中分子1和2显示出有希望的抑制活性，IC 50值约为10 μ M，但溶解度和代谢稳定性低。在命中系列勘探的早期阶段，嘧啶核被各种修饰，以获得具有更好的物理化学特征的活性化合物。特别地，化合物13显示出与命中分子1和2相当的Wnt抑制活性，具有改善的物理化学性质。因此，这一系列的化合物可以被认为是一个有前途的起点，为经典的Wnt途径的新型小分子抑制剂的设计。(C)2015爱思唯尔有限公司版权所有。
The canonical Wnt signaling pathway plays a fundamental role in embryonic as well as in adult development. Consequently, dysregulation of the pathway has been linked to a wide spectrum of pathological conditions. In a program aimed at the identification of small molecule inhibitors of the canonical Wnt pathway we identified a series of 2-aminopyrimidine derivatives which specifically inhibited the pathway with minimal or no sign of cellular toxicity. The hit molecules 1 and 2 showed promising inhibitory activity with IC50 values of approximately 10 mu M, but low solubility and metabolic stability. During the early stage of the hit series exploration, the pyrimidine core was variously decorated to obtain active compounds with a better physico-chemical profile. In particular, compound 13 showed Wnt inhibition activity comparable to hit molecules 1 and 2, with improved physico-chemical properties. Therefore, this series of compounds may be considered a promising starting point for the design of novel small molecule inhibitors of the canonical Wnt pathway. (C) 2015 Elsevier Ltd. All rights reserved.