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Small‐Molecule Inhibitors of Shp2 Phosphatase as Potential Chemotherapeutic Agents for Glioblastoma: A Minireview
ChemMedChem ( IF 3.6 ) Pub Date : 2020-11-19 , DOI: 10.1002/cmdc.202000706
Rangan Mitra 1 , Senthil R Ayyannan 1
Affiliation  

Glioblastoma multiforme (GBM) is a dreadful cancer characterised by poor prognosis, low survival rate and difficult clinical correlations. Several signalling pathways and molecular mediators are known to precipitate GBM, and small‐molecular targets of these mediators have become a favoured thrust area for researchers to develop potent anti‐GBM drugs. Shp2, an important phosphatase of the nonreceptor type protein tyrosine phosphatase (PTPN) subfamily is responsible for master regulation of several such signalling pathways in normal and glioma cells. Thus, inhibition of Shp2 is a logical strategy for the design and development of anti‐neoplastic drugs against GBM. Though tapping the full potential of Shp2 binding sites has been challenging, nevertheless, many synthetic and natural scaffolds have been documented as possessing potent and selective anti‐Shp2 activities in biochemical and cellular assays, through either active‐site or allosteric binding. Most of these scaffolds share a few common pharmacophoric features, a thorough study of which is useful in paving the way for the design and development of improved Shp2 inhibitors. This minireview summarizes the current scenario of potent small‐molecule Shp2 inhibitors and emphasizes the anti‐GBM potential of some important scaffolds that have shown promising GBM‐specific activity in in vitro and in vivo models, thus proving their efficacy in GBM therapy. This review could guide researchers to design new and improved anti‐Shp2 pharmacophores and develop them as anti‐GBM agents by employing GBM‐centric drug‐discovery protocols.

中文翻译:

Shp2 磷酸酶的小分子抑制剂作为胶质母细胞瘤的潜在化学治疗剂:小综述

多形性胶质母细胞瘤 (GBM) 是一种可怕的癌症,其特点是预后差、存活率低和临床相关性困难。已知有几种信号通路和分子介质可导致 GBM 沉淀,这些介质的小分子靶点已成为研究人员开发有效抗 GBM 药物的有利推动领域。Shp2 是非受体型蛋白酪氨酸磷酸酶 (PTPN) 亚家族的一种重要磷酸酶,负责正常和神经胶质瘤细胞中几种此类信号通路的主调节。因此,抑制 Shp2 是设计和开发针对 GBM 的抗肿瘤药物的合理策略。尽管充分挖掘 Shp2 结合位点的潜力一直具有挑战性,但是,许多合成和天然支架已被证明在生化和细胞分析中通过活性位点或变构结合具有有效和选择性的抗 Shp2 活性。这些支架中的大多数都具有一些共同的药效学特征,对其进行深入研究有助于为改进的 Shp2 抑制剂的设计和开发铺平道路。这篇小综述总结了强效小分子 Shp2 抑制剂的当前情况,并强调了一些重要支架的抗 GBM 潜力,这些支架在体外和体内模型中显示出有希望的 GBM 特异性活性,从而证明了它们在 GBM 治疗中的功效。该综述可以指导研究人员设计新的和改进的抗 Shp2 药效团,并通过采用以 GBM 为中心的药物发现协议将它们开发为抗 GBM 药物。
更新日期:2020-11-19
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