Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, 00161, Italy.
Department of Molecular Medicine, Sapienza University of Rome, Rome, 00161, Italy.
Sci Rep. 2017 May 19;7(1):2213. doi: 10.1038/s41598-017-02316-9.
Notch signaling is considered a rational target in the therapy of several cancers, particularly those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL). Although currently available Notch-blocking agents are showing anti-tumor activity in preclinical studies, they are not effective in all the patients and often cause severe side-effects, limiting their widespread therapeutic use. Here, by functional and biological analysis of the most representative molecules of an in house library of natural products, we have designed and synthetized the chalcone-derivative 8 possessing Notch inhibitory activity at low micro molar concentration in T-ALL cell lines. Structure-activity relationships were afforded for the chalcone scaffold. Short term treatments with compound 8 resulted in a dose-dependent decrease of Notch signaling activity, halted cell cycle progression and induced apoptosis, thus affecting leukemia cell growth. Taken together, our data indicate that 8 is a novel Notch inhibitor, candidate for further investigation and development as an additional therapeutic option against Notch-dependent cancers.
Notch 信号通路被认为是多种癌症治疗的合理靶点，特别是那些具有 Notch 功能获得性突变的癌症，包括 T 细胞急性淋巴细胞白血病（T-ALL）。尽管目前可用的 Notch 阻断剂在临床前研究中显示出抗肿瘤活性，但它们并非对所有患者都有效，而且经常会引起严重的副作用，限制了它们的广泛治疗用途。在这里，我们通过对天然产物内部文库中最具代表性的分子进行功能和生物学分析，设计并合成了查尔酮衍生物 8，该化合物在 T-ALL 细胞系中以低微摩尔浓度具有 Notch 抑制活性。我们还对查尔酮支架进行了结构活性关系研究。短期用化合物 8 处理会导致 Notch 信号通路活性呈剂量依赖性下降，阻止细胞周期进程并诱导细胞凋亡，从而影响白血病细胞的生长。综上所述，我们的数据表明，8 是一种新型的 Notch 抑制剂，可进一步研究和开发，作为对抗 Notch 依赖性癌症的另一种治疗选择。
