富含亮氨酸的五肽重复序列蛋白 (LRPPRC)、信号转导子和转录激活子 3 (STAT3) 以及细胞周期蛋白依赖性激酶 1 (CDK1) 是癌症治疗的有希望的治疗靶点。但临床上缺乏LRPPRC、STAT3、CDK1的有效抑制剂。我们前期的研究证明5,7,4'-Trimethoxyflavone (TMF)是一种新型的LRPPRC/STAT3/CDK1抑制剂。但陈皮中TMF的提取率较低，细胞和小鼠体内TMF的剂量较高。在此，TMF的结构修饰产生了两个系列的TMF衍生物，包括3'位(7a-m)和3',8位(11a-m)取代的磺酰胺。在所有化合物中，7e、7k、11e 和 11g 在体外表现出有效、广谱和强效的抗癌剂。此外，7e、7k、11e和11g在体内表现出比TMF和临床使用的化疗药物卡培他滨更好的抗肿瘤效果，且无明显毒性。机制研究表明，11g可以与LRPPRC、STAT3和CDK1结合，解离LRPPRC-JAK2-STAT3和JAK2-STAT3-CDK1复合物，从而抑制JAK2/STAT3信号通路。这些发现表明，11g 可能作为三靶点（LRPPRC、STAT3 和 CDK1）抑制剂作为癌症治疗的主要化合物。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), signal transducer and activator of transcription 3 (STAT3), and cyclin-dependent kinase 1 (CDK1) are promising therapeutic targets for cancer treatment. However, there is a lack of effective inhibitors of LRPPRC, STAT3, and CDK1 in clinic. Our previous study has proved that 5,7,4'-Trimethoxyflavone (TMF) is a novel inhibitor of LRPPRC/STAT3/CDK1. However, the extraction rate of TMF from Tangerine Peel is quite low, and the doses of TMF in cells and mice are rather high. Herein, structural modifications of TMF have led to two series of TMF derivatives including sulfonamide substituted at 3'-position (7a-m) and 3',8-position (11a-m). Among all compounds, 7e, 7k, 11e, and 11g exhibited as effective, broad-spectrum, and potent anticancer agents in vitro. Moreover, 7e, 7k, 11e, and 11g showed better antitumor effects than TMF and clinical used chemotherapy drug capecitabine in vivo with no obvious toxicity. Mechanism studies showed that 11g could bind to LRPPRC, STAT3, and CDK1 to disassociate the LRPPRC-JAK2-STAT3 and JAK2-STAT3-CDK1 complexes, resulting in suppression of JAK2/STAT3 signaling pathway. These findings suggest that 11g may serve as a leading compound for cancer therapy as a triple-target (LRPPRC, STAT3, and CDK1) inhibitor.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.