Identification of a novel heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) ligand that disrupts HnRNPA2B1/nucleic acid interactions to inhibit the MDMX-p53 axis in gastric cancer

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. [Display omitted] •Our study identified XI-011 as a heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) ligand that binds the RRM1 domain.•Disrupting the hnRNPA2B1-nucleic acid interactions was an effective means to inhibit the transcription of MDMX.•We presented that targeting hnRNPA2B1 to regulate the MDMX-p53 axis is a promising strategy in gastric cancer treatment.