School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
Pharmacol Res. 2023 Mar;189:106696. doi: 10.1016/j.phrs.2023.106696. Epub 2023 Feb 13.
Gastric carcinoma is a highly malignant tumor that still lacks effective molecular targets. Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an essential oncogenic driver overexpressed in various cancers. The potential role of hnRNPA2B1 in oncotherapy has not been revealed because of the absence of active chemical molecules. In this study, we identified the pseudourea derivative XI-011 as a novel hnRNPA2B1 ligand using chemical proteomics. An interaction study indicated that XI-011 could bind the nucleotide-binding domain to disrupt the recruitment of hnRNPA2B1 to the promoter and untranslated region of the murine double minute X (MDMX) gene, thereby inhibiting its transcription. In addition, chemical targeting of hnRNPA2B1 recovered inactivated p53 and enhanced the therapeutic efficacy of apatinib in vivo. This work presented a novel strategy to restore p53 activity for the treatment of gastric cancers via chemically targeting hnRNPA2B1.
胃癌是一种高度恶性的肿瘤，目前仍然缺乏有效的分子靶点。异质性核核糖核蛋白 A2B1（hnRNPA2B1）是一种在多种癌症中过度表达的重要致癌驱动因子。由于缺乏有效的化学分子，hnRNPA2B1 在肿瘤治疗中的潜在作用尚未被揭示。在这项研究中，我们使用化学蛋白质组学方法鉴定了假尿素衍生物 XI-011 作为一种新型 hnRNPA2B1 配体。相互作用研究表明，XI-011 可以与核苷酸结合域结合，从而破坏 hnRNPA2B1 募集到鼠双微体 X（MDMX）基因启动子和非翻译区，从而抑制其转录。此外，靶向 hnRNPA2B1 的化学药物可以恢复失活的 p53 并增强阿帕替尼在体内的治疗效果。这项工作提出了一种通过化学靶向 hnRNPA2B1 恢复 p53 活性治疗胃癌的新策略。
