胃癌是一种高度恶性的肿瘤，仍然缺乏有效的分子靶点。异质核核糖核蛋白A2B1（hnRNPA2B1）是一种在各种癌症中过度表达的重要致癌驱动因子。由于缺乏活性化学分子，hnRNPA2B1在肿瘤治疗中的潜在作用尚未被揭示。在这项研究中，我们利用化学蛋白质组学的方法，鉴定出一种假脲衍生物XI-011作为一种新型的hnRNPA2B1配体。交互作用研究表明，XI-011能够结合核苷酸结合域，破坏hnRNPA2B1对小鼠双分钟X（MDMX）基因启动子和未翻译区的招募，从而抑制其转录。此外，通过化学靶向hnRNPA2B1，恢复失活的p53，并增强体内apatini的治疗效果。本研究开创了一个恢复p53活性治疗胃癌的新策略，这是通过化学靶向hnRNPA2B1实现的。版权所有 © 2023 The Authors。由Elsevier Ltd.出版。保留所有权利。

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.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.